徳島大学 / 教育研究者総覧 --- 吉丸哲郎

個人のホームページ

https://researchmap.jp/fukunanajin (researchmap)

専門分野

○	医学 (Medicine)

研究テーマ

○

著書・論文

著書:

1.	吉丸哲郎, 片桐豊雅 : 乳がんにおける新規がん抑制因子不活化機構の解明と創薬研究, 2018年9月.

学術論文(審査論文):

1.	Shun-ichi Toki, Tetsuro Yoshimaru, Yosuke Matsushita, Hitoshi Aibara, Masaya Ono, Koichi Tsuneyama, Koichi Sairyo and Toyomasa Katagiri : The survival and proliferation of osteosarcoma cells are dependent on the mitochondrial BIG3-PHB2 complex formation., Cancer Science, Vol.112, No.10, 4208-4219, 2021. (要約) Previous studies reported the critical role of the brefeldin A-inhibited guanine nucleotide exchange protein 3-prohibitin 2 (BIG3-PHB2) complex in modulating estrogen signaling activation in breast cancer cells, yet its pathophysiological roles in osteosarcoma (OS) cells remain elusive. Here, we report a novel function of BIG3-PHB2 in OS malignancy. BIG3-PHB2 complexes were localized mainly in mitochondria in OS cells, unlike in estrogen-dependent breast cancer cells. Depletion of endogenous BIG3 expression by small interfering RNA (siRNA) treatment led to significant inhibition of OS cell growth. Disruption of BIG3-PHB2 complex formation by treatment with specific peptide inhibitor also resulted in significant dose-dependent suppression of OS cell growth, migration, and invasion resulting from G2/M-phase arrest and in PARP cleavage, ultimately leading to PARP-1/apoptosis-inducing factor (AIF) pathway activation-dependent apoptosis in OS cells. Subsequent proteomic and bioinformatic pathway analyses revealed that disruption of the BIG3-PHB2 complex might lead to downregulation of inner mitochondrial membrane protein complex activity. Our findings indicate that the mitochondrial BIG3-PHB2 complex might regulate PARP-1/AIF pathway-dependent apoptosis during OS cell proliferation and progression and that disruption of this complex may be a promising therapeutic strategy for OS. (キーワード) Animals / アポトーシス (apoptosis) / Apoptosis Inducing Factor / Bone Neoplasms / Cell Line, Tumor / Cell Movement / Cell Proliferation / Cell Survival / Cell-Penetrating Peptides / Databases, Factual / Down-Regulation / G2 Phase Cell Cycle Checkpoints / Gene Silencing / Guanine Nucleotide Exchange Factors / Humans / M Phase Cell Cycle Checkpoints / Membrane Proteins / Mice / Mice, Nude / ミトコンドリア (mitochondria) / Mitochondrial Membranes / Neoplasm Invasiveness / Neoplasm Transplantation / Osteosarcoma / Poly (ADP-Ribose) Polymerase-1 / Prohibitins / RNA, Small Interfering / Repressor Proteins (徳島大学機関リポジトリ) ● Metadata: 116580 (出版サイトへのリンク) ● Publication site (DOI): 10.1111/cas.15099 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 34363714 ● Search Scopus @ Elsevier (PMID): 34363714 ● Search Scopus @ Elsevier (DOI): 10.1111/cas.15099 (徳島大学機関リポジトリ: 116580, DOI: 10.1111/cas.15099, PubMed: 34363714)
2.	Tetsuro Yoshimaru, Yusuke Nakamura and Toyomasa Katagiri : Functional genomics for breast cancer drug target discovery., Journal of Human Genetics, Vol.66, No.9, 927-935, 2021. (要約) Breast cancer is a heterogeneous disease that develops through a multistep process via the accumulation of genetic/epigenetic alterations in various cancer-related genes. Current treatment options for breast cancer patients include surgery, radiotherapy, and chemotherapy including conventional cytotoxic and molecular-targeted anticancer drugs for each intrinsic subtype, such as endocrine therapy and antihuman epidermal growth factor receptor 2 (HER2) therapy. However, these therapies often fail to prevent recurrence and metastasis due to resistance. Overall, understanding the molecular mechanisms of breast carcinogenesis and progression will help to establish therapeutic modalities to improve treatment. The recent development of comprehensive omics technologies has led to the discovery of driver genes, including oncogenes and tumor-suppressor genes, contributing to the development of molecular-targeted anticancer drugs. Here, we review the development of anticancer drugs targeting cancer-specific functional therapeutic targets, namely, MELK (maternal embryonic leucine zipper kinase), TOPK (T-lymphokine-activated killer cell-originated protein kinase), and BIG3 (brefeldin A-inhibited guanine nucleotide-exchange protein 3), as identified through comprehensive breast cancer transcriptomics. (キーワード) Antineoplastic Agents / Breast Neoplasms / Drug Discovery / Female / Genomics / Humans (徳島大学機関リポジトリ) ● Metadata: 117231 (出版サイトへのリンク) ● Publication site (DOI): 10.1038/s10038-021-00962-6 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 34285339 ● Search Scopus @ Elsevier (PMID): 34285339 ● Search Scopus @ Elsevier (DOI): 10.1038/s10038-021-00962-6 (徳島大学機関リポジトリ: 117231, DOI: 10.1038/s10038-021-00962-6, PubMed: 34285339)
3.	Ryuichiro Kimura, Tetsuro Yoshimaru, Yosuke Matsushita, Taisuke Matsuo, Masaya Ono, Jae-Hyun Park, Mitsunori Sasa, Yasuo Miyoshi, Yusuke Nakamura and Toyomasa Katagiri : The GALNT6‑LGALS3BP axis promotes breast cancer cell growth., International Journal of Oncology, Vol.56, No.2, 581-595, 2019. (要約) Polypeptide N‑acetylgalactosaminyltransferase 6 (GALNT6), which is involved in the initiation of O‑glycosylation, has been reported to play crucial roles in mammary carcinogenesis through binding to several substrates; however, its biological roles in mediating growth‑promoting effects remain unknown. The present study demonstrated a crucial pathophysiological role of GALNT6 through its O‑glycosylation of lectin galactoside‑binding soluble 3 binding protein (LGALS3BP), a secreted growth‑promoting glycoprotein, in breast cancer growth. The Cancer Genome Atlas data analysis revealed that high expression levels of GALNT6 were significantly associated with poor prognosis of breast cancer. GALNT6 O‑glycosylated LGALS3BP in breast cancer cells, whereas knockdown of GALNT6 by siRNA led to the inhibition of both the O‑glycosylation and secretion of LGALS3BP, resulting in the suppression of breast cancer cell growth. Notably, LGALS3BP is potentially O‑glycosylated at three sites (T556, T571 and S582) by GALNT6, thereby promoting autocrine cell growth, whereas the expression of LGALS3BP with three Ala substitutions (T556A, T571A and S582A) in cells drastically reduced GALNT6‑dependent LGALS3BP O‑glycosylation and secretion, resulting in suppression of autocrine growth‑promoting effect. The findings of the present study suggest that the GALNT6‑LGALS3BP axis is crucial for breast cancer cell proliferation and may be a therapeutic target and biomarker for mammary tumors. (出版サイトへのリンク) ● Publication site (DOI): 10.3892/ijo.2019.4941 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 31894262 ● Search Scopus @ Elsevier (PMID): 31894262 ● Search Scopus @ Elsevier (DOI): 10.3892/ijo.2019.4941 (DOI: 10.3892/ijo.2019.4941, PubMed: 31894262)
4.	Takeru Chigira, Satoru Nagatoishi, Hiroyuki Takeda, Tetsuro Yoshimaru, Toyomasa Katagiri and Kouhei Tsumoto : Biophysical characterization of the breast cancer-related BIG3-PHB2 interaction: Effect of non-conserved loop region of BIG3 on the structure and the interaction., Biochemical and Biophysical Research Communications, Vol.518, No.1, 183-189, 2019. (要約) Brefeldin A-inhibited guanine nucleotide-exchange protein 3 (BIG3) interacts with and inhibits the tumor suppressor function of prohibitin-2 (PHB2), and recent in vivo studies have demonstrated that the BIG3-PHB2 interaction is a promising target for breast cancer therapy. However, little biophysical characterization on BIG3 and its interaction with PHB2 has been reported. Here we compared the calculated 8-class secondary structure of the N-terminal domains of BIG family proteins and identified a loop region unique to BIG3. Our biophysical characterization demonstrated that this loop region significantly affects the colloidal and thermodynamic stability of BIG3 and the thermodynamic and kinetic profile of its interaction with PHB2. These results establish a model for the BIG3-PHB2 interaction and an entry for drug discovery for breast cancer. (出版サイトへのリンク) ● Publication site (DOI): 10.1016/j.bbrc.2019.08.028 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 31421830 ● Search Scopus @ Elsevier (PMID): 31421830 ● Search Scopus @ Elsevier (DOI): 10.1016/j.bbrc.2019.08.028 (DOI: 10.1016/j.bbrc.2019.08.028, PubMed: 31421830)
5.	Kei Daizumoto, Tetsuro Yoshimaru, Yosuke Matsushita, Tomoya Fukawa, Hisanori Uehara, Masaya Ono, Masato Komatsu, Hiro-omi Kanayama and Toyomasa Katagiri : A DDX31/mutant-p53/EGFR axis promotes multistep progression of muscle invasive bladder cancer, Cancer Research, Vol.78, No.9, 2233-2247, 2018. (要約) The p53 and EGFR pathways are frequently altered in bladder cancer, yet their contributions to its progression remain elusive. Here we report that DEAD box polypeptide 31 (DDX31) plays a critical role in the multistep progression of muscle-invasive bladder cancer (MIBC) through its sequential interactions with mutant p53 (mutp53) and EGFR. In early MIBC cells, nuclear DDX31-bound mutp53/SP1 enhanced mutp53 transcriptional activation, leading to migration and invasion of MIBC. Cytoplasmic DDX31 also bound EGFR and phospho-nucleolin in advanced MIBC, leading to EGFR-Akt signaling activation. High expression of both cytoplasmic DDX31 and p53 proteins correlated with poor prognosis in patients with MIBC, and blocking the DDX31/NCL interaction resulted in downregulation of EGFR/Akt signaling, eliciting an antitumor effect against bladder cancer. These findings reveal that DDX31 cooperates with mutp53 and EGFR to promote progression of MIBC, and inhibition of DDX31/NCL formation may lead to potential treatment strategies for advanced MIBC. DDX31 cooperates with mutp53 and EGFR to promote progression of muscle invasive bladder cancer. . (徳島大学機関リポジトリ) ● Metadata: 111804 (出版サイトへのリンク) ● Publication site (DOI): 10.1158/0008-5472.CAN-17-2528 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 29440146 ● Search Scopus @ Elsevier (PMID): 29440146 ● Search Scopus @ Elsevier (DOI): 10.1158/0008-5472.CAN-17-2528 (徳島大学機関リポジトリ: 111804, DOI: 10.1158/0008-5472.CAN-17-2528, PubMed: 29440146)
6.	Yoshimasa Miyagawa, Yosuke Matsushita, Hiromu Suzuki, Masato Komatsu, Tetsuro Yoshimaru, Ryuichiro Kimura, Ayako Yanai, Junko Honda, Akira Tangoku, Mitsunori Sasa, Yasuo Miyoshi and Toyomasa Katagiri : Frequent downregulation of LRRC26 by epigenetic alterations is involved in the malignant progression of triple-negative breast cancer., International Journal of Oncology, 2018. (要約) Triple-negative breast cancer (TNBC), defined as breast cancer lacking estrogen- and progesterone‑receptor expression and human epidermal growth factor receptor 2 (HER2) amplification, is a heterogeneous disease. RNA-sequencing analysis of 15 TNBC specimens and The Cancer Genome Atlas-TNBC dataset analysis identified the frequent downregulation of leucine-rich repeat-containing 26 (LRRC26), which negatively regulates nuclear factor-κB (NF-κB) signaling, in TNBC tissues. Quantitative polymerase chain reaction and bisulfite pyrosequencing analyses revealed that LRRC26 was frequently silenced in TNBC tissues and cell lines as a result of promoter methylation. LRRC26 expression was restored by 5-aza-2'-deoxycytidine (5'-aza-dC) treatment in HCC1937 TNBC cells, which lack LRRC26 expression. Notably, small interfering RNA-mediated knockdown of LRRC26 expression significantly enhanced the anchorage-independent growth, invasion and migration of HCC70 cells, whereas ectopic overexpression of LRRC26 in BT20 cells suppressed their invasion and migration. Conversely, neither knockdown nor overexpression of LRRC26 had an effect on cell viability in the absence of tumor necrosis factor-α (TNF-α) stimulation. Meanwhile, overexpression of LRRC26 caused the reduction of TNF-α-mediated NF-κB luciferase reporter activity, whereas depleting LRRC26 expression resulted in the upregulation of TNF-α-mediated NF-κB downstream genes [interleukin-6 (IL-6), IL-8 and C-X-C motif chemokine ligand-1]. Taken together, these findings demonstrate that LRRC26 is frequently downregulated in TNBC due to DNA methylation and that it suppresses the TNF-α-independent anchorage-independent growth, invasion and migration of TNBC cells. Loss of LRRC26 function may be a critical event in the aggressiveness of TNBC cells through a TNF-α/NF-κB-independent mechanism. (出版サイトへのリンク) ● Publication site (DOI): 10.3892/ijo.2018.4301 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 29512727 ● Search Scopus @ Elsevier (PMID): 29512727 ● Search Scopus @ Elsevier (DOI): 10.3892/ijo.2018.4301 (DOI: 10.3892/ijo.2018.4301, PubMed: 29512727)
7.	Tetsuro Yoshimaru, Masaya Ono, Yoshimi Bando, Yi-An Chen, Kenji Mizuguchi, Hiroshi Shima, Masato Komatsu, Issei Imoto, Keisuke Izumi, Junko Honda, Yasuo Miyoshi, Mitsunori Sasa and Toyomasa Katagiri : A-kinase anchoring protein BIG3 coordinates oestrogen signalling in breast cancer cells., Nature Communications, Vol.8, No.15427, 2017. (要約) Approximately 70% of breast cancer cells express oestrogen receptor alpha (ER). Previous studies have shown that the Brefeldin A-inhibited guanine nucleotide-exchange protein 3-prohibitin 2 (BIG3-PHB2) complex has a crucial role in these cells. However, it remains unclear how BIG3 regulates the suppressive activity of PHB2. Here we demonstrate that BIG3 functions as an A-kinase anchoring protein that binds protein kinase A (PKA) and the isoform of the catalytic subunit of protein phosphatase 1 (PP1C), thereby dephosphorylating and inactivating PHB2. E2-induced PKA-mediated phosphorylation of BIG3-S305 and -S1208 serves to enhance PP1C activity, resulting in E2/ER signalling activation via PHB2 inactivation due to PHB2-S39 dephosphorylation. Furthermore, an analysis of independent cohorts of ER-positive breast cancers patients reveal that both BIG3 overexpression and PHB2-S39 dephosphorylation are strongly associated with poor prognosis. This is the first demonstration of the mechanism of E2/ER signalling activation via the BIG3-PKA-PP1C tri-complex in breast cancer cells. (徳島大学機関リポジトリ) ● Metadata: 112449 (出版サイトへのリンク) ● Publication site (DOI): 10.1038/ncomms15427 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 28555617 ● Summary page in Scopus @ Elsevier: 2-s2.0-85019970677 (徳島大学機関リポジトリ: 112449, DOI: 10.1038/ncomms15427, PubMed: 28555617, Elsevier: Scopus)
8.	Tetsuro Yoshimaru, Keisuke Aihara, Masato Komatsu, Yosuke Matsushita, Yasumasa Okazaki, Shinya Toyokuni, Junko Honda, Mitsunori Sasa, Yasuo Miyoshi, Akira Otaka and Toyomasa Katagiri : Stapled BIG3 helical peptide ERAP potentiates anti-tumour activity for breast cancer therapeutics., Scientific Reports, Vol.7, No.1, 1821, 2017. (要約) Estradiol (E2) and the oestrogen receptor-alpha (ER) signalling pathway play pivotal roles in the proliferative activity of breast cancer cells. Recent findings show that the brefeldin A-inhibited guanine nucleotide-exchange protein 3-prohibitin 2 (BIG3-PHB2) complex plays a crucial role in E2/ER signalling modulation in breast cancer cells. Moreover, specific inhibition of the BIG3-PHB2 interaction using the ER activity-regulator synthetic peptide (ERAP: 165-177 amino acids), derived from -helical BIG3 sequence, resulted in a significant anti-tumour effect. However, the duration of this effect was very short for viable clinical application. We developed the chemically modified ERAP using stapling methods (stapledERAP) to improve the duration of its antitumour effects. The stapledERAP specifically inhibited the BIG3-PHB2 interaction and exhibited long-lasting suppressive activity. Its intracellular localization without the membrane-permeable polyarginine sequence was possible via the formation of a stable -helix structure by stapling. Tumour bearing-mice treated daily or weekly with stapledERAP effectively prevented the BIG3-PHB2 interaction, leading to complete regression of E2-dependent tumours in vivo. Most importantly, combination of stapledERAP with tamoxifen, fulvestrant, and everolimus caused synergistic inhibitory effects on growth of breast cancer cells. Our findings suggested that the stapled ERAP may be a promising anti-tumour drug to suppress luminal-type breast cancer growth. (徳島大学機関リポジトリ) ● Metadata: 112387 (出版サイトへのリンク) ● Publication site (DOI): 10.1038/s41598-017-01951-6 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 28500289 ● Search Scopus @ Elsevier (PMID): 28500289 ● Search Scopus @ Elsevier (DOI): 10.1038/s41598-017-01951-6 (徳島大学機関リポジトリ: 112387, DOI: 10.1038/s41598-017-01951-6, PubMed: 28500289)
9.	Yuki Shikata, Tetsuro Yoshimaru, Masato Komatsu, Hiroto Katoh, Reiko Sato, Shuhei Kanagaki, Yasumasa Okazaki, Shinya Toyokuni, Etsu Tashiro, Shumpei Ishikawa, Toyomasa Katagiri and Masaya Imoto : Protein kinase A inhibition facilitates the antitumor activity of xanthohumol, a valosin-containing protein inhibitor., Cancer Science, Vol.108, No.4, 785-794, 2017. (要約) Xanthohumol (XN), a simple prenylated chalcone, can be isolated from hops and has the potential to be a cancer chemopreventive agent against several human tumor cell lines. We previously identified valosin-containing protein (VCP) as a target of XN; VCP can also play crucial roles in cancer progression and prognosis. Therefore, we investigated the molecular mechanisms governing the contribution of VCP to the antitumor activity of XN. Several human tumor cell lines were treated with XN to investigate which human tumor cell lines are sensitive to XN. Several cell lines exhibited high sensitivity to XN both in vitro and in vivo. shRNA screening and bioinformatics analysis identified that the inhibition of the adenylate cyclase (AC) pathway synergistically facilitated apoptosis induced by VCP inhibition. These results suggest there is crosstalk between the AC pathway and VCP function, and targeting both VCP and the AC pathway is a potential chemotherapeutic strategy for a subset of tumor cells. This article is protected by copyright. All rights reserved. (徳島大学機関リポジトリ) ● Metadata: 112374 (出版サイトへのリンク) ● Publication site (DOI): 10.1111/cas.13175 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 28122154 ● Search Scopus @ Elsevier (PMID): 28122154 ● Search Scopus @ Elsevier (DOI): 10.1111/cas.13175 (徳島大学機関リポジトリ: 112374, DOI: 10.1111/cas.13175, PubMed: 28122154)
10.	Namhee Kim, Tetsuro Yoshimaru, Yi-An Chen, Taisuke Matsuo, Masato Komatsu, Yasuo Miyoshi, Eiji Tanaka, Mitsunori Sasa, Kenji Mizuguchi and Toyomasa Katagiri : BIG3 Inhibits the Estrogen-Dependent Nuclear Translocation of PHB2 via Multiple Karyopherin-Alpha Proteins in Breast Cancer Cells., PLoS ONE, Vol.10, No.6, 2015. (要約) We recently reported that brefeldin A-inhibited guanine nucleotide-exchange protein 3 (BIG3) binds Prohibitin 2 (PHB2) in cytoplasm, thereby causing a loss of function of the PHB2 tumor suppressor in the nuclei of breast cancer cells. However, little is known regarding the mechanism by which BIG3 inhibits the nuclear translocation of PHB2 into breast cancer cells. Here, we report that BIG3 blocks the estrogen (E2)-dependent nuclear import of PHB2 via the karyopherin alpha (KPNA) family in breast cancer cells. We found that overexpressed PHB2 interacted with KPNA1, KPNA5, and KPNA6, thereby leading to the E2-dependent translocation of PHB2 into the nuclei of breast cancer cells. More importantly, knockdown of each endogenous KPNA by siRNA caused a significant inhibition of E2-dependent translocation of PHB2 in BIG3-depleted breast cancer cells, thereby enhancing activation of estrogen receptor alpha (ER). These data indicated that BIG3 may block the KPNAs (KPNA1, KPNA5, and KPNA6) binding region(s) of PHB2, thereby leading to inhibition of KPNAs-mediated PHB2 nuclear translocation in the presence of E2 in breast cancer cells. Understanding this regulation of PHB2 nuclear import may provide therapeutic strategies for controlling E2/ER signals in breast cancer cells. (徳島大学機関リポジトリ) ● Metadata: 109497 (出版サイトへのリンク) ● Publication site (DOI): 10.1371/journal.pone.0127707 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 26052702 ● Summary page in Scopus @ Elsevier: 2-s2.0-84936761474 (徳島大学機関リポジトリ: 109497, DOI: 10.1371/journal.pone.0127707, PubMed: 26052702, Elsevier: Scopus)
11.	Tetsuro Yoshimaru, Masato Komatsu, Yasuo Miyoshi, Junko Honda, Mitsunori Sasa and Toyomasa Katagiri : Therapeutic advances in BIG3-PHB2 inhibition targeting the crosstalk between estrogen and growth factors in breast cancer., Cancer Science, Vol.106, No.5, 550-558, 2015. (要約) Our previous studies demonstrated that specific inhibition of the BIG3-PHB2 complex, which is a critical modulator in estrogen (E2) signaling, using ERAP, a dominant negative peptide inhibitor, leads to suppression of E2-dependent estrogen receptor (ER) alpha activation through the reactivation of the tumor suppressive activity of PHB2. Here, we report that ERAP has significant suppressive effects against synergistic activation caused by the crosstalk between E2 and growth factors associated with intrinsic or acquired resistance to anti-estrogen tamoxifen in breast cancer cells. Intrinsic PHB2 released from BIG3 by ERAP effectively disrupted each interaction of membrane-associated ERα and insulin-like growth factor 1 receptor beta (IGF-1Rβ), EGFR, PI3K or human epidermal growth factor 2 (HER2) in the presence of E2 and the growth factors IGF or EGF, followed by inhibited the activation of IGF-1Rβ, EGFR or HER2, and reduced Akt, MAPK and ERα phosphorylation levels, resulting in significant suppression of proliferation of ERα-positive breast cancer cells in vitro and in vivo. More importantly, combined treatment with ERAP and tamoxifen led to a synergistic suppression of signaling that was activated by crosstalk between E2 and growth factors or HER2 amplification. Taken together, our findings suggest that the specific inhibition of BIG3-PHB2 is a novel potential therapeutic approach for the treatment of tamoxifen-resistant breast cancers activated by the crosstalk between E2 and growth factor signaling, especially in premenopausal women. (キーワード) Animals / Breast Neoplasms / Cell Line, Tumor / Cell-Penetrating Peptides / Drug Resistance, Neoplasm / Estrogen Receptor alpha / Female / Guanine Nucleotide Exchange Factors / Humans / Insulin-Like Growth Factor I / Mice, Nude / Molecular Targeted Therapy / リン酸化 (phosphorylation) / Receptor, ErbB-2 / Repressor Proteins / シグナル伝達 (signal transduction) / Tamoxifen / Xenograft Model Antitumor Assays (出版サイトへのリンク) ● Publication site (DOI): 10.1111/cas.12654 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 25736224 ● Summary page in Scopus @ Elsevier: 2-s2.0-84929712454 (DOI: 10.1111/cas.12654, PubMed: 25736224, Elsevier: Scopus)
12.	Tetsuro Yoshimaru, Masato Komatsu, Etsu Tashiro, Masaya Imoto, Hiroyuki Osada, Yasuo Miyoshi, Junko Honda, Mitsunoi Sasa and Toyomasa Katagiri : Xanthohumol suppresses oestrogen-signalling in breast cancer through the inhibition of BIG3-PHB2 interactions., Scientific Reports, Vol.4, 7355, 2014. (要約) Xanthohumol (XN) is a natural anticancer compound that inhibits the proliferation of oestrogen receptor- (ER)-positive breast cancer cells. However, the precise mechanism of the antitumour effects of XN on oestrogen (E2)-dependent cell growth, and especially its direct target molecule(s), remain(s) largely unknown. Here, we focus on whether XN directly binds to the tumour suppressor protein prohibitin 2 (PHB2), forming a novel natural antitumour compound targeting the BIG3-PHB2 complex and acting as a pivotal modulator of E2/ER signalling in breast cancer cells. XN treatment effectively prevented the BIG3-PHB2 interaction, thereby releasing PHB2 to directly bind to both nuclear- and cytoplasmic ER. This event led to the complete suppression of the E2-signalling pathways and ER-positive breast cancer cell growth both in vitro and in vivo, but did not suppress the growth of normal mammary epithelial cells. Our findings suggest that XN may be a promising natural compound to suppress the growth of luminal-type breast cancer. (出版サイトへのリンク) ● Publication site (DOI): 10.1038/srep07355 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 25483453 ● Search Scopus @ Elsevier (PMID): 25483453 ● Search Scopus @ Elsevier (DOI): 10.1038/srep07355 (DOI: 10.1038/srep07355, PubMed: 25483453)
13.	Taisuke Matsuo, Le Tan Dat, Masato Komatsu, Tetsuro Yoshimaru, Kei Daizumoto, Saburo Sone, Yasuhiko Nishioka and Toyomasa Katagiri : Early growth response 4 is involved in cell proliferation of small cell lung cancer through transcriptional activation of its downstream genes., PLoS ONE, Vol.9, No.11, e113606, 2014. (要約) Small cell lung cancer (SCLC) is aggressive, with rapid growth and frequent bone metastasis; however, its detailed molecular mechanism remains poorly understood. Here, we report the critical role of early growth factor 4 (EGR4), a DNA-binding, zinc-finger transcription factor, in cell proliferation of SCLC. EGR4 overexpression in HEK293T cells conferred significant upregulation of specific splice variants of the parathyroid hormone-related protein (PTHrP) gene, resulting in enhancement of the secretion of PTHrP protein, a known mediator of osteolytic bone metastasis. More importantly, depletion of EGR4 expression by siRNA significantly suppressed growth of the SCLC cell lines, SBC-5, SBC-3 and NCI-H1048. On the other hand, introduction of EGR4 into NIH3T3 cells significantly enhanced cell growth. We identified four EGR4 target genes, SAMD5, RAB15, SYNPO and DLX5, which were the most significantly downregulated genes upon depletion of EGR4 expression in all of the SCLC cells examined, and demonstrated the direct recruitment of EGR4 to their promoters by ChIP and luciferase reporter analysis. Notably, knockdown of the expression of these genes by siRNA remarkably suppressed the growth of all the SCLC cells. Taken together, our findings suggest that EGR4 likely regulates the bone metastasis and proliferation of SCLC cells via transcriptional regulation of several target genes, and may therefore be a promising target for the development of anticancer drugs for SCLC patients. (キーワード) Animals / Cell Line, Tumor / Cell Proliferation / Chromatin Immunoprecipitation / Early Growth Response Transcription Factors / HEK293 Cells / Homeodomain Proteins / Humans / Interleukin-6 / Interleukin-8 / Lung Neoplasms / Mice / Microfilament Proteins / NIH 3T3 Cells / Paracrine Communication / Parathyroid Hormone-Related Protein / RANK Ligand / Small Cell Lung Carcinoma / Transcription Factors / Transcriptional Activation / Up-Regulation / rab GTP-Binding Proteins (出版サイトへのリンク) ● Publication site (DOI): 10.1371/journal.pone.0113606 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 25411851 ● Summary page in Scopus @ Elsevier: 2-s2.0-84912060344 (DOI: 10.1371/journal.pone.0113606, PubMed: 25411851, Elsevier: Scopus)
14.	Yi-An Chen, Yoichi Murakami, Shandar Ahmad, Tetsuro Yoshimaru, Toyomasa Katagiri and Kenji Mizuguchi : Brefeldin A-inhibited guanine nucleotide-exchange protein 3 (BIG3) is predicted to interact with its partner through an ARM-type -helical structure., BMC Research Notes, Vol.7, No.1, 435, 2014. (要約) The combined results of the structure and interaction prediction led to a novel hypothesis that one of the predicted helices of BIG3 might play an important role in binding to PHB2 and thereby preventing its translocation to the nucleus. This hypothesis has been subsequently verified experimentally. (キーワード) Amino Acid Sequence / Binding Sites / Female / Guanine Nucleotide Exchange Factors / Humans / Molecular Sequence Data / Neoplasm Proteins / Protein Binding / Protein Structure, Secondary / Protein Structure, Tertiary / Repressor Proteins / Sequence Alignment / Sequence Homology, Amino Acid (徳島大学機関リポジトリ) ● Metadata: 114782 (出版サイトへのリンク) ● Publication site (DOI): 10.1186/1756-0500-7-435 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 24997568 ● Search Scopus @ Elsevier (PMID): 24997568 ● Search Scopus @ Elsevier (DOI): 10.1186/1756-0500-7-435 (徳島大学機関リポジトリ: 114782, DOI: 10.1186/1756-0500-7-435, PubMed: 24997568)
15.	Taisuke Matsuo, Masato Komatsu, Tetsuro Yoshimaru, Kazuma Kiyotani, Yasuo Miyoshi, Mitsunori Sasa and Toyomasa Katagiri : Involvement of B3GALNT2 overexpression in the cell growth of breast cancer., International Journal of Oncology, Vol.44, No.2, 427-434, 2013. (要約) A number of glycosyltransferases have been identified and biologically characterized in cancer cells, yet their exact pathophysiological functions are largely unknown. Here, we report the critical role of 1,3-N-acetylgalactosaminyltransferase II (B3GALNT2), which transfers N-acetylgalactosamine (GalNAc) in a 1,3 linkage to N-acetylglucosamine, in the growth of breast cancer cells. Comprehensive transcriptomics, quantitative PCR and northern blot analyses indicated this molecule to be exclusively upregulated in the majority of breast cancers. Knockdown of B3GALNT2 expression by small interfering RNA attenuated cell growth and induced apoptosis in breast cancer cells. Overexpression of B3GALNT2 in HEK293T cells prompted secretion of the gene product into the culture medium, suggesting that B3GALNT2 is potentially a secreted protein. Furthermore, we demonstrated that B3GALNT2 is N-glycosylated on both Asn-116 and Asn-174 and that this modification is necessary for its secretion in breast cancer cells. Our findings suggest that this molecule represents a promising candidate for the development of a novel therapeutic targeting drug and a potential diagnostic tumor marker for patients with breast cancer, especially TNBC. (出版サイトへのリンク) ● Publication site (DOI): 10.3892/ijo.2013.2187 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 24285400 ● Summary page in Scopus @ Elsevier: 2-s2.0-84894481440 (DOI: 10.3892/ijo.2013.2187, PubMed: 24285400, Elsevier: Scopus)
16.	Masato Komatsu, Tetsuro Yoshimaru, Taisuke Matsuo, Kazuma Kiyotani, Yasuo Miyoshi, Toshihito Tanahashi, Kazuhito Rokutan, Rui Yamaguchi, Ayumu Saito, Seiya Imoto, Satoru Miyano, Yusuke Nakamura, Mitsunori Sasa, Mitsuo Shimada and Toyomasa Katagiri : Molecular features of triple negative breast cancer cells by genome-wide gene expression profiling analysis., International Journal of Oncology, Vol.42, No.2, 478-506, 2013. (要約) Triple negative breast cancer (TNBC) has a poor outcome due to the lack of beneficial therapeutic targets. To clarify the molecular mechanisms involved in the carcinogenesis of TNBC and to identify target molecules for novel anticancer drugs, we analyzed the gene expression profiles of 30 TNBCs as well as 13 normal epithelial ductal cells that were purified by laser-microbeam microdissection. We identified 301 and 321 transcripts that were significantly upregulated and downregulated in TNBC, respectively. In particular, gene expression profile analyses of normal human vital organs allowed us to identify 104 cancer-specific genes, including those involved in breast carcinogenesis such as NEK2, PBK and MELK. Moreover, gene annotation enrichment analysis revealed prominent gene subsets involved in the cell cycle, especially mitosis. Therefore, we focused on cell cycle regulators, asp (abnormal spindle) homolog, microcephaly-associated (Drosophila) (ASPM) and centromere protein K (CENPK) as novel therapeutic targets for TNBC. Small-interfering RNA-mediated knockdown of their expression significantly attenuated TNBC cell viability due to G1 and G2/M cell cycle arrest. Our data will provide a better understanding of the carcinogenesis of TNBC and could contribute to the development of molecular targets as a treatment for TNBC patients. (出版サイトへのリンク) ● Publication site (DOI): 10.3892/ijo.2012.1744 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 23254957 ● Search Scopus @ Elsevier (PMID): 23254957 ● Search Scopus @ Elsevier (DOI): 10.3892/ijo.2012.1744 (DOI: 10.3892/ijo.2012.1744, PubMed: 23254957)
17.	Tetsuro Yoshimaru, Masato Komatsu, Taisuke Matsuo, Yi-An Chen, Yoichi Murakami, Kenji Mizuguchi, Eiichi Mizohata, Tsuyoshi Inoue, Miki Akiyama, Rui Yamaguchi, Seiya Imoto, Satoru Miyano, Yasuo Miyoshi, Mitsunori Sasa, Yusuke Nakamura and Toyomasa Katagiri : Targeting BIG3-PHB2 interaction to overcome tamoxifen resistance in breast cancer cells., Nature Communications, Vol.4, 2443, 2013. (要約) The acquisition of endocrine resistance is a common obstacle in endocrine therapy of patients with oestrogen receptor- (ER)-positive breast tumours. We previously demonstrated that the BIG3-PHB2 complex has a crucial role in the modulation of oestrogen/ER signalling in breast cancer cells. Here we report a cell-permeable peptide inhibitor, called ERAP, that regulates multiple ER-signalling pathways associated with tamoxifen resistance in breast cancer cells by inhibiting the interaction between BIG3 and PHB2. Intrinsic PHB2 released from BIG3 by ERAP directly binds to both nuclear- and membrane-associated ER, which leads to the inhibition of multiple ER-signalling pathways, including genomic and non-genomic ER activation and ER phosphorylation, and the growth of ER-positive breast cancer cells both in vitro and in vivo. More importantly, ERAP treatment suppresses tamoxifen resistance and enhances tamoxifen responsiveness in ER-positive breast cancer cells. These findings suggest inhibiting the interaction between BIG3 and PHB2 may be a new therapeutic strategy for the treatment of luminal-type breast cancer. (キーワード) Amino Acid Sequence / Antineoplastic Agents / Binding Sites / Cell Line, Tumor / Cell Membrane / Cell Nucleus / Cell-Penetrating Peptides / Drug Resistance, Neoplasm / Estrogen Receptor alpha / Female / Gene Expression Regulation, Neoplastic / Histone-Lysine N-Methyltransferase / Humans / Molecular Sequence Data / Phosphorylation / Protein Binding / Repressor Proteins / Selective Estrogen Receptor Modulators / Signal Transduction / Tamoxifen (出版サイトへのリンク) ● Publication site (DOI): 10.1038/ncomms3443 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 24051437 ● Search Scopus @ Elsevier (PMID): 24051437 ● Search Scopus @ Elsevier (DOI): 10.1038/ncomms3443 (DOI: 10.1038/ncomms3443, PubMed: 24051437)
18.	Le T Dat, Taisuke Matsuo, Tetsuro Yoshimaru, Souji Kakiuchi, Hisatsugu Goto, Masaki Hanibuchi, Takuya Kuramoto, Yasuhiko Nishioka, Saburo Sone and Toyomasa Katagiri : Identification of genes potentially involved in bone metastasis by genome-wide gene expression profile analysis of non-small cell lung cancer in mice, International Journal of Oncology, Vol.40, No.5, 1455-1469, 2012. (要約) Lung cancer is commonly associated with multi-organ metastasis, and the bone is a frequent metastatic site for lung cancer. However, the molecular mechanism of organ-specific metastasis remains poorly understood. To elucidate this issue, we analyzed in this study genome-wide gene expression profiles of 15 metastatic lesions from three organs (bone, lung and liver) in a mouse model with multi-organ metastasis properties of human non-small cell lung cancer cells (ACC-LC319/bone2), using a combination of laser-microbeam microdissection and DNA microarrays. We identified 299 genes that could potentially be involved in the organ-selective nature of lung cancer metastasis. Among them, 77 were bone-specifically expressed elements, including genes involved in cell adhesion, cytoskeleton/cell motility, extracellular matrix remodeling and cell-cell signaling as well as genes already known to be involved in the bone metastasis of breast cancers. Quantitative RT-PCR confirmed the specific upregulation of eight genes in bone metastasis tumors, suggesting that these genes may be involved in bone metastasis. Our findings should be helpful for a better understanding of the molecular aspects of the metastatic process in different organs, and could lead to molecular target-based anticancer drugs and prevention of metastasis, especially bone metastasis. (キーワード) Animals / Bone Neoplasms / Carcinoma, Non-Small-Cell Lung / Cell Line, Tumor / Cluster Analysis / Gene Expression Profiling / Gene Expression Regulation, Neoplastic / Genetic Predisposition to Disease / Genome-Wide Association Study / Humans / Laser Capture Microdissection / Lung Neoplasms / Male / Mice / Mice, SCID / Neoplasm Invasiveness / Neoplasm Transplantation / Oligonucleotide Array Sequence Analysis / Phenotype / Real-Time Polymerase Chain Reaction / Reverse Transcriptase Polymerase Chain Reaction (出版サイトへのリンク) ● Publication site (DOI): 10.3892/ijo.2012.1348 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 22294041 ● Search Scopus @ Elsevier (PMID): 22294041 ● Search Scopus @ Elsevier (DOI): 10.3892/ijo.2012.1348 (DOI: 10.3892/ijo.2012.1348, PubMed: 22294041)
19.	Satoshi Nunomura, Yasuhiro Gon, Tetsuro Yoshimaru, Junichi Kashiwakura, Toshiaki Kawakami and Chisei Ra : FcepsilonRI beta-chain ITAM amplifies PI3K-signaling to ensure synergistic degranulation response via FcepsilonRI and adenosine receptors., European Journal of Immunology, Vol.40, No.4, 1205-1217, 2010. (要約) Simultaneous stimulation with antigen and adenosine in mast cells induces a synergistic degranulation response at a low antigen dose that is insufficient to cause secretion by itself. This kind of stimulation is thought to be relevant to the immediate asthmatic response upon bronchial challenge with low-dose allergen. In this context, FcepsilonRI- and adenosine receptor-mediated signalings cooperate to increase degranulation in mast cells. In the present study, we prepared mast cells that have mutations (Y219F/Y225F/Y229F) in three tyrosine residues of the FcepsilonRI beta-chain (FcRbeta)-ITAM in order to elucidate the molecular mechanisms of degranulation response synergistically elicited by costimulation with low-dose antigen and adenosine. Introduction of mutations in the FcRbeta-ITAM abolished the synergistic degranulation response. Upon costimulation with low-dose antigen and adenosine, tyrosine phosphorylation of Grb2-associated binder 2, which is located upstream of PI3K-signaling, was significantly increased, but severely diminished in FcRbeta-ITAM mutant cells. These findings indicate that FcRbeta acts as a critical element in mast cell synergistic degranulation response through FcepsilonRI and adenosine receptors, and that PI3K-signaling through FcRbeta-ITAM is a crucial participant in augmentation of FcepsilonRI-mediated degranulation by adenosine. (出版サイトへのリンク) ● Publication site (DOI): 10.1002/eji.200939651 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 20101614 ● Search Scopus @ Elsevier (PMID): 20101614 ● Search Scopus @ Elsevier (DOI): 10.1002/eji.200939651 (DOI: 10.1002/eji.200939651, PubMed: 20101614)
20.	Toshio Inoue, Yoshihiro Suzuki, Kazuya Mizuno, Kazuko Nakata, Tetsuro Yoshimaru and Chisei Ra : SHP-1 exhibits a pro-apoptotic function in antigen-stimulated mast cells: positive regulation of mitochondrial death pathways and negative regulation of survival signaling pathways., Molecular Immunology, Vol.47, No.2-3, 222-232, 2009. (要約) Src homology region 2 domain-containing phosphatase-1 (SHP-1) is known to act as a negative signal modulator in mast cells but its roles in cell survival and cell death are poorly understood. We previously reported that SHP-1 also positively regulates mast cell activation signaling by acting as an adaptor protein. In the present study, we examined whether SHP-1 plays a role in antigen (Ag)-induced activation-induced mast cell death. Bone marrow-derived mast cells (BMMCs) from SHP-1-deficient motheaten (me) mice (me-BMMCs) were significantly less susceptible to store-operated Ca(2+) channel (SOC) activation, Ag-induced cell death and DNA fragmentation than BMMCs from their wild-type littermates (WT-BMMCs). Subsequent experiments revealed that the differences in these cellular susceptibilities to SOC activation and cell death resulted from the extent of the mitochondrial permeability transition pore (mPTP) opening. Specifically, mPTP opening was sufficiently persistent in WT-BMMCs to evoke mitochondrial integrity disruption, while mPTP opening was too transient to cause the minimal mitochondrial integrity collapse in me-BMMCs. In addition, pro-survival signaling including activation of mitogen-activated protein kinases (MAPKs) such as the extracellular signal-regulated protein kinases, c-Jun NH(2) terminal kinases and p38 and the expression of Bcl-x(L) were significantly prolonged in me-BMMCs compared with WT-BMMCs. Taken together, these data demonstrate that a lack of SHP-1 prevents the mPTP-mediated mitochondrial integrity collapse and augments anti-apoptotic signaling such as MAPKs and Bcl-x(L). These findings suggest that SHP-1 positively regulates mitochondrial death pathways and negatively regulates pro-survival signaling pathways. (キーワード) Animals / Antigens / アポトーシス (apoptosis) / Bone Marrow Cells / Calcium Channels / Cell Survival / Ion Channel Gating / Mast Cells / Mice / ミトコンドリア (mitochondria) / Mitochondrial Membrane Transport Proteins / Protein Tyrosine Phosphatase, Non-Receptor Type 6 / シグナル伝達 (signal transduction) (出版サイトへのリンク) ● Publication site (DOI): 10.1016/j.molimm.2009.09.033 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 19875169 ● Search Scopus @ Elsevier (PMID): 19875169 ● Search Scopus @ Elsevier (DOI): 10.1016/j.molimm.2009.09.033 (DOI: 10.1016/j.molimm.2009.09.033, PubMed: 19875169)
21.	Toshio Inoue, Yoshihiro Suzuki, Tetsuro Yoshimaru and Chisei Ra : Nitric Oxide positively regulates Ag (I)-induced Ca(2+) influx and mast cell activation: role of a Nitric Oxide Synthase-independent pathway., Journal of Leukocyte Biology, Vol.86, No.6, 1365-1375, 2009. (要約) NO is generated by NOS activity and known to act as a negative regulator of mast cell activation. We reported previously that Ag (I) directly evokes mast cell degranulation and LTC(4) release via Ca(2+) influx through thiol-sensitive, store-independent channels. Here, we report that NO generated independently of NOS activity mediates the store-independent Ca(2+) influx. Exposure of mast cells to Ag (I) resulted in increased intracellular NO levels and NO(2)(-)/NO(3)(-) contents in the extracellular fluid. The NO increase was blocked by NO scavenger Hb and DTT but not by NOS inhibitors such as amino-BH(4) and L-NAME. This NO production occurred independently of the Src family kinase and PI3K activities, both of which were necessary for antigen-induced, NOS-dependent NO production. Hb and DTT reduced Ag (I)-induced beta-hexosaminidase release and LTC(4) release, whereas the NO scavengers and NOS inhibitors augmented antigen-induced mediator release. Moreover, Hb and DTT, but not the NOS inhibitors, abolished the Ag (I)-induced Ca(2+) influx, and none of the drugs blocked CRAC channel activity. Finally, Ag (I)-induced Ca(2+) influx was distinct from LTCC activity in terms of its sensitivities to wortmannin and LTCC antagonists and the effects of Ca(v)1.2 LTCC gene silencing. These data show that NOS-independent NO regulates mast cell activation positively via a unique store-independent Ca(2+) influx pathway. The present findings suggest multiple sources and functions of NO in mast cell biology. (キーワード) カルシウム (calcium) / Calcium Channels, L-Type / Degranulation / Dithiothreitol / Enzyme Inhibitors / Leukotriene C4 / Mast Cells / Nitric Oxide / Nitric Oxide Synthase / Silver (出版サイトへのリンク) ● Publication site (DOI): 10.1189/jlb.0609387 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 19706839 ● Search Scopus @ Elsevier (PMID): 19706839 ● Search Scopus @ Elsevier (DOI): 10.1189/jlb.0609387 (DOI: 10.1189/jlb.0609387, PubMed: 19706839)
22.	Yoshihiro Suzuki, Tetsuro Yoshimaru, Toshio Inoue and Chisei Ra : Discrete generations of intracellular hydrogen peroxide and superoxide in antigen-stimulated mast cells: reciprocal regulation of store-operated Ca2+ channel activity., Molecular Immunology, Vol.46, No.11-12, 2200-2209, 2009. (要約) Mast cells and T cells produce reactive oxygen species (ROS) after stimulation with the high-affinity IgE receptor (Fc epsilon RI) and T cell receptor. A growing body of evidence suggests the existence of ROS-regulated intracellular and/or plasma membrane Ca(2+) channels in these cells but their molecular entities remain to be identified. Here, we report that store-operated Ca(2+) channel (SOC) activity is regulated by superoxide (O(2)(-)) and hydrogen peroxide (H(2)O(2)) in mast cells. MnTBaP (Mn(III)tetrakis(4-benzoic acid)porphyrin) and ebselen (2-phenyl-1,2-benziso-selenazol-3(2H)-one) selectively blocked the generation of O(2)(-) and H(2)O(2), respectively, in antigen-stimulated cells. The H(2)O(2) generation was dependent on the Src family kinase (SFK) and phosphatidylinositol-3-kinase (PI3K) activities but independent of extracellular Ca(2+), and the Fc epsilon RI beta-chain immunoreceptor tyrosine-based activation motif played an essential role. On the other hand, O(2)(-) generation was strictly dependent on extracellular Ca(2+), but negatively regulated by the SFK and PI3K activities. Inhibition of O(2)(-) generation resulted in increased H(2)O(2) generation and reduced SOC activity, although it had a minimal effect on endoplasmic reticulum Ca(2+) store depletion. On the contrary, inhibition of H(2)O(2) generation resulted in increased intracellular O(2)(-) generation and augmented SOC activity. The findings suggest that O(2)(-) and H(2)O(2), which are generated by separate signaling pathways/sources, reciprocally regulate SOC activity in mast cells. Such generations of multiple oxidant species and their distinct roles in the regulation of SOC activity may facilitate the fine tuning of Ca(2+) signaling in mast cells. (キーワード) 1-Phosphatidylinositol 3-Kinase / カルシウム (calcium) / Calcium Channels / Cell Degranulation / Endoplasmic Reticulum / Hydrogen Peroxide / Mast Cells / Mice / Receptors, IgE / Superoxides / src-Family Kinases (出版サイトへのリンク) ● Publication site (DOI): 10.1016/j.molimm.2009.04.013 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 19467708 ● Search Scopus @ Elsevier (PMID): 19467708 ● Search Scopus @ Elsevier (DOI): 10.1016/j.molimm.2009.04.013 (DOI: 10.1016/j.molimm.2009.04.013, PubMed: 19467708)
23.	Yoshihiro Suzuki, Tetsuro Yoshimaru, Toshio Inoue and Chisei Ra : Ca v 1.2 L-type Ca2+ channel protects mast cells against activation-induced cell death by preventing mitochondrial integrity disruption., Molecular Immunology, Vol.46, No.11-12, 2370-2380, 2009. (要約) In non-excitable cells, store-operated Ca(2+) channels (SOCs) are the principal routes of Ca(2+) entry. Recently, store-independent Ca(2+) channels which are pharmacologically and/or immunologically similar to L-type Ca(2+) channels (LTCCs) have been shown to exist in various hematopoietic cells, including T cells, B cells and neutrophils. We previously reported that mast cells express LTCCs which regulate mast cell effector responses in a distinct manner from SOCs. In the present study, we examined the possible role for LTCCs in mast cell survival. Both RBL-2H3 mast cells and bone marrow-derived mast cells underwent considerable apoptosis after treatment with thapsigargin (Tg) but not stimulation through the high-affinity IgE receptor (Fc epsilon RI). The LTCC-selective antagonists such as nifedipine greatly augmented Fc epsilon RI-mediated apoptosis, while the LTCC-selective agonist (S)-BayK8644 blocked Tg-induced apoptosis. The modulation of apoptosis was accompanied by altered mitochondrial integrity, as measured with the mitochondrial membrane potential, cytochrome c release and caspase-3/7 activation. Fc epsilon RI stimulation induced mitochondrial Ca(2+) ([Ca(2+)](m)) entry through both SOCs and LTCCs, while Tg evoked [Ca(2+)](m) entry through LTCCs but not SOCs. The LTCC-selective antagonists blocked [Ca(2+)](m) entry, whereas (S)-BayK8644 augmented Tg-induced [Ca(2+)](m) entry. Moreover, blockade of the expression of the alpha(1C) subunit of Ca(v)1.2 LTCC using small-interfering RNA strongly augmented Fc epsilon RI-mediated apoptosis, mitochondrial integrity, and mitochondrial Ca(2+) collapse, and abolished the protective effects of (S)-BayK8644 against Tg-induced apoptosis. These findings suggest that Ca(v)1.2 LTCC protects mast cells against activation-induced cell death by preventing mitochondrial integrity disruption. (キーワード) 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Animals / アポトーシス (apoptosis) / Bone Marrow Cells / Calcium Channels, L-Type / Calcium Signaling / Cell Line / Cell Survival / Ion Channel Gating / Mast Cells / Membrane Potential, Mitochondrial / Mice / ミトコンドリア (mitochondria) / Nifedipine / Protein Subunits / Receptors, IgE / Thapsigargin (出版サイトへのリンク) ● Publication site (DOI): 10.1016/j.molimm.2009.03.017 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 19447492 ● Search Scopus @ Elsevier (PMID): 19447492 ● Search Scopus @ Elsevier (DOI): 10.1016/j.molimm.2009.03.017 (DOI: 10.1016/j.molimm.2009.03.017, PubMed: 19447492)
24.	Toshio Inoue, Yoshihiro Suzuki, Tetsuro Yoshimaru and Chisei Ra : Ca2+-dependent mast cell death induced by Ag (I) via cardiolipin oxidation and ATP depletion., Journal of Leukocyte Biology, Vol.86, No.1, 167-179, 2009. (要約) In genetically susceptible humans and/or experimental animals, ions of heavy metals, Hg (II), Au (III), and Ag (I) have been shown to strongly induce autoimmunity, in which mast cells have been implicated to play a role. Here, we demonstrate that Ag (I) application results in mast cell death through a unique Ca(2+)- and mitochondria-dependent pathway. As cellular susceptibilities to Ag (I) cytotoxicity varied considerably, we analyzed the cell death pathway in the low and high responding cells. In the low responding cells, long application (e.g., 20 h) of Ag (I) at concentrations (>or=30 microM) induced cell death, which was accompanied by mitochondrial membrane depolarization, cyt c release, and caspase-3/7 activation but was not prevented by selective inhibitors of caspase-3/7 and the mitochondrial permeability transition. The cell death was preceded by elevations in the cytoplasmic and mitochondrial Ca(2+) levels, and Ca(2+) responses and cell death were prevented by thiol reagents, including DTT, N-acetylcysteine, and reduced glutathione monoethyl ester. In the high responding cells, Ag (I) evoked considerable cell death by necrosis within 1 h, without inducing caspase activation, and this cell death was reduced significantly by depleting extracellular but not intracellular Ca(2+). Moreover, Ag (I) strongly induced Ca(2+)-dependent CL oxidation and intracellular ATP depletion, both of which were blocked by thiol reagents. These results suggest that Ag (I) activates thiol-dependent Ca(2+) channels, thereby promoting Ca(2+)-dependent CL oxidation, cyt c release, and ATP depletion. This necrotic cell death may play roles in Ag-induced inflammation and autoimmune disorders. (キーワード) Adenosine Triphosphate / Animals / Autoimmunity / カルシウム (calcium) / Calcium Channels / Cardiolipins / Cytochromes c / Inflammation / Mast Cells / Mice / Mice, Inbred C57BL / ミトコンドリア (mitochondria) / Necrosis / 酸化と還元 (oxidation and reduction) / Silver (出版サイトへのリンク) ● Publication site (DOI): 10.1189/jlb.1108691 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 19401388 ● Search Scopus @ Elsevier (PMID): 19401388 ● Search Scopus @ Elsevier (DOI): 10.1189/jlb.1108691 (DOI: 10.1189/jlb.1108691, PubMed: 19401388)
25.	Kana Togo, Yoshihiro Suzuki, Tetsuro Yoshimaru, Toshio Inoue, Tadashi Terui, Toyoko Ochiai and Chisei Ra : Aspirin and salicylates modulate IgE-mediated leukotriene secretion in mast cells through a dihydropyridine receptor-mediated Ca(2+) influx., Clinical Immunology, Vol.131, No.1, 145-156, 2009. (要約) Aspirin is a well-known nonsteroidal anti-inflammatory drug (NSAID) that may potentiate some acute allergies and causes adverse immunological reactions collectively referred to as aspirin intolerance. Aspirin intolerance is accompanied by increased leukotriene (LT) synthesis, and high levels of serum IgE are a risk factor for NSAID sensitivity. Here we demonstrate that aspirin modulates LTC(4) secretion in mast cells. Therapeutic levels of aspirin and salicylates (<or=0.3 mM, i.e., the concentrations observed in vivo in the use of antipyretic analgesic) increased IgE-mediated LTC(4) secretion. Aspirin-induced stimulation was accompanied by increased Ser-505 phosphorylation of cytosolic phospholipase A(2), which occurred independently of extracellular signal-regulated protein kinase-1/2 and p38 mitogen-activated protein kinase pathways. Aspirin also increased IgE-mediated Ca(2+) influx, whereas aspirin at concentrations of >or=0.3 mM dose-dependently reduced Ca(2+) store emptying and Ca(2+) release-activated Ca(2+) channel activation. Instead, aspirin facilitated a dihydropyridine receptor-mediated Ca(2+) influx, resulting in increased LTC(4) secretion. This novel action of aspirin may play roles in exacerbation of immediate allergy and aspirin intolerance. (キーワード) Animals / Anti-Inflammatory Agents, Non-Steroidal / Aspirin / Blotting, Western / カルシウム (calcium) / Calcium Channels, L-Type / Cell Line / Enzyme-Linked Immunosorbent Assay / Flow Cytometry / Fluorometry / Immunoglobulin E / Leukotriene C4 / Mast Cells / Membrane Potential, Mitochondrial / Mice / Mice, Inbred C3H / Mitogen-Activated Protein Kinase 3 / Phospholipases A2 / Rats / Salicylates / p38 Mitogen-Activated Protein Kinases (出版サイトへのリンク) ● Publication site (DOI): 10.1016/j.clim.2008.09.008 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 19144570 ● Search Scopus @ Elsevier (PMID): 19144570 ● Search Scopus @ Elsevier (DOI): 10.1016/j.clim.2008.09.008 (DOI: 10.1016/j.clim.2008.09.008, PubMed: 19144570)
26.	Tetsuro Yoshimaru, Yoshihiro Suzuki, Toshio Inoue and Chisei Ra : L-type Ca2+ channels in mast cells: activation by membrane depolarization and distinct roles in regulating mediator release from store-operated Ca2+ channels., Molecular Immunology, Vol.46, No.7, 1267-1277, 2009. (要約) Store-operated Ca(2+) channels (SOCs) are considered to be the principal route of Ca(2+) influx in non-excitable cells. We have previously shown that in mast cells IgE+antigen (Ag) induces a dihydropyridine (DHP)-sensitive Ca(2+) influx independently of Ca(2+) store depletion. Since the DHP receptor is the alpha subunit of L-type Ca(2+) channels (LTCCs), we examined the possible role of LTCCs in mast cell activation. Mast cells exhibited substantial expression of the alpha(1C) (Ca(V)1.2) subunit mRNA and protein on their cell surface. IgE+Ag-induced Ca(2+) influx was substantially reduced by the LTCC inhibitor nifedipine, and enhanced by the LTCC activator (S)-BayK8644, whereas these agents had minimal effects on thapsigargin (TG)-induced Ca(2+) influx. These LTCC-modulating agents regulated IgE+Ag-induced cell activation but not TG-induced cell activation. Inhibition of SOCs by 2-aminoethoxydiphenyl borate reduced both degranulation and production of cytokines, including interleukin-13 and tumor necrosis factor-alpha, whereas LTCC modulation reciprocally regulated degranulation and cytokine production. IgE+Ag, but not TG, induced substantial plasma membrane depolarization, which stimulated a DHP-sensitive Ca(2+) response. Moreover, IgE+Ag-, but not TG-induced mitochondrial Ca(2+) increase was regulated by LTCC modulators. Finally, gene silencing analyses using small interfering RNA revealed that the alpha(1C) (Ca(V)1.2) LTCC mediated the pharmacological effects of the LTCC-modulating agents. These results demonstrate that mast cells express LTCCs, which becomes activated by membrane depolarization to regulate cytosolic and mitochondrial Ca(2+), thereby controlling mast cell activation in a distinct manner from SOCs. (キーワード) Animals / Antigens / Antigens, Surface / Calcium Channels, L-Type / Calcium Signaling / Cells, Cultured / Immunoglobulin E / Mast Cells / Membrane Potentials / Mice / Mice, Inbred C57BL / Rats / Thapsigargin (出版サイトへのリンク) ● Publication site (DOI): 10.1016/j.molimm.2008.11.011 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 19128833 ● Search Scopus @ Elsevier (PMID): 19128833 ● Search Scopus @ Elsevier (DOI): 10.1016/j.molimm.2008.11.011 (DOI: 10.1016/j.molimm.2008.11.011, PubMed: 19128833)
27.	Kazuko Nakata, Tetsuro Yoshimaru, Yoshihiro Suzuki, Toshio Inoue, Chisei Ra, Hidetaka Yakura and Kazuya Mizuno : Positive and negative regulation of high affinity IgE receptor signaling by Src homology region 2 domain-containing phosphatase 1., The Journal of Immunology, Vol.181, No.8, 5414-5424, 2008. (要約) Src homology region 2 domain-containing phosphatase 1 (SHP-1), a cytoplasmic protein tyrosine phosphatase, plays an important role for the regulation of signaling from various hematopoietic cell receptors. Although SHP-1 is shown to be a negative signal modulator in mast cells, its precise molecular mechanisms are not well defined. To elucidate how SHP-1 regulates mast cell signaling, we established bone marrow-derived mast cells from SHP-1-deficient motheaten and wild-type mice and analyzed downstream signals induced by cross-linking of high affinity IgE receptor, Fc epsilonRI. Upon Fc epsilonRI ligation, motheaten-derived bone marrow-derived mast cells showed enhanced tyrosine phosphorylation of Src homology region 2 domain-containing leukocyte protein of 76 kDa (SLP-76) and linker for activation of T cells, activation of mitogen-activated protein kinases and gene transcription and production of cytokine. Because the activity of Syk, responsible for the phosphorylation of SLP-76 and linker for activation of T cells, is comparable irrespective of SHP-1, both molecules might be substrates of SHP-1 in mast cells. Interestingly, the absence of SHP-1 expression disrupted the association between SLP-76 and phospholipase Cgamma, which resulted in the decreased phospholipase Cgamma phosphorylation, calcium mobilization, and degranulation. Collectively, these results suggest that SHP-1 regulates Fc epsilonRI-induced downstream signaling events both negatively and positively by functioning as a protein tyrosine phosphatase and as an adaptor protein contributing to the formation of signaling complex, respectively. (キーワード) Adaptor Proteins, Signal Transducing / Animals / Calcium / Cell Degranulation / Extracellular Signal-Regulated MAP Kinases / Gene Expression Regulation, Enzymologic / Intracellular Signaling Peptides and Proteins / Lymphocyte Activation / Mast Cells / Mice / Mice, Mutant Strains / Phospholipase C gamma / Phosphoproteins / Phosphorylation / Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Protein-Tyrosine Kinases / Receptors, IgE / Signal Transduction / T-Lymphocytes (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 18832698 ● Summary page in Scopus @ Elsevier: 2-s2.0-54049146268 (PubMed: 18832698, Elsevier: Scopus)
28.	Tetsuro Yoshimaru, Yoshihiro Suzuki, Toshio Inoue, Shigeru Nishida and Chisei Ra : Extracellular superoxide released from mitochondria mediates mast cell death by advanced glycation end products., Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, Vol.1783, No.12, 2332-2343, 2008. (要約) Advanced glycation end products (AGEs) accumulate during aging and to higher extents under pathological conditions such as diabetes. Since we previously showed that mast cells expressed the AGE-binding protein, receptor for AGEs (RAGE) on their cell surface, we examined whether AGE affected mast cell survival. Herein, we demonstrate that mast cells undergo apoptosis in response to AGE. Glycated albumin (GA), an AGE, but not stimulation with the high-affinity IgE receptor (FcepsilonRI), can induce mast cell death, as measured by annexin V/propidium iodide double-staining. GA (> or =0.1 mg/ml) exhibited this pro-apoptotic activity in a concentration-dependent manner. GA and FcepsilonRI stimulation increased the cytosolic Ca(2+) levels to a similar extent, whereas GA, but not FcepsilonRI stimulation, caused mitochondrial Ca(2+) overload and membrane potential collapse, resulting in mitochondrial integrity disruption, cytochrome c release and caspase-3/7 activation. In addition, GA, but not FcepsilonRI stimulation, induced extracellular release of superoxide from mitochondria, and this release played a key role in the disruption of Ca(2+) homeostasis. Knockdown of RAGE expression using small interfering RNA abolished GA-induced apoptosis, mitochondrial Ca(2+) overload, and superoxide release, demonstrating that RAGE mediates the GA-induced mitochondrial death pathway. AGE-induced mast cell apoptosis may contribute to the immunocompromised and inflammatory conditions. (キーワード) Animals / Apoptosis / Bone Marrow / Calcium / Caspase 3 / Caspase 7 / Cells, Cultured / Cytochromes c / Enzyme Activation / Glycosylation / Glycosylation End Products, Advanced / Humans / Leukemia, Basophilic, Acute / Mast Cells / Membrane Potential, Mitochondrial / Mice / Mice, Inbred C3H / Mice, Inbred C57BL / Mitochondria / Mitochondrial Membrane Transport Proteins / RNA, Messenger / RNA, Small Interfering / Rats / Receptors, IgG / Receptors, Immunologic / Reverse Transcriptase Polymerase Chain Reaction / Serum Albumin / Superoxides (出版サイトへのリンク) ● Publication site (DOI): 10.1016/j.bbamcr.2008.08.010 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 18822320 ● Search Scopus @ Elsevier (PMID): 18822320 ● Search Scopus @ Elsevier (DOI): 10.1016/j.bbamcr.2008.08.010 (DOI: 10.1016/j.bbamcr.2008.08.010, PubMed: 18822320)
29.	Takashi Matsui, Satoshi Nunomura, Toshibumi Shimokawa, Tetsuro Yoshimaru and Chisei Ra : Functionality of the IgA Fc receptor (FcalphaR, CD89) is down-regulated by extensive engagement of FcepsilonRI., Clinical Immunology, Vol.129, No.1, 155-162, 2008. (要約) Besides mast cells and basophils, the high-affinity IgE Fc receptor (FcepsilonRI) is exclusively expressed on certain FcalphaR (IgA Fc receptor)-expressing immune cells such as neutrophils in allergic patients. Transfected rat basophilic leukemia cell line (RBL-2H3) co-expressing FcepsilonRI and FcalphaR was analyzed for effects of simultaneous receptor engagement by their specific antibodies on degranulation and signaling. Whereas supraoptimal FcepsilonRI engagement decreased degranulation, which is known as a bell-shaped dose-response curve, such inhibitory effect was not observed with FcalphaR engagement. However, simultaneous engagement of FcepsilonRI and FcalphaR showed that supraoptimal FcepsilonRI engagement down-regulates FcalphaR-mediated degranulation. This inhibition was associated with extensive phosphorylation of inositol polyphosphate 5'-phosphatase SHIP1 and FcepsilonRIbeta, and reversed by adding actin-depolymerizing drug, latrunculin B. The results suggest an endogenous mechanism by which FcalphaR functionality is down-regulated in an 'allergic environment' where FcepsilonRI is co-expressed and extensively cross-linked on FcalphaR-expressing effector cells. (キーワード) Actins / Animals / Antigens, CD / Bicyclo Compounds, Heterocyclic / Cell Degranulation / Cell Line, Tumor / Down-Regulation / Humans / Phosphoric Monoester Hydrolases / Phosphorylation / Rats / Receptors, Fc / Receptors, IgE / Thiazolidines (出版サイトへのリンク) ● Publication site (DOI): 10.1016/j.clim.2008.07.003 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 18700185 ● Search Scopus @ Elsevier (PMID): 18700185 ● Search Scopus @ Elsevier (DOI): 10.1016/j.clim.2008.07.003 (DOI: 10.1016/j.clim.2008.07.003, PubMed: 18700185)
30.	Satoshi Nunomura, Tetsuro Yoshimaru and Chisei Ra : Na-Tosyl-Phe chloromethyl ketone prevents granule movement and mast cell synergistic degranulation elicited by costimulation of antigen and adenosine., Life Sciences, Vol.83, No.7-8, 242-249, 2008. (要約) Adenosine has been shown to enhance mast cell degranulation when added together with an antigen. Such augmentation of mast cell activation is relevant to exacerbation of allergic asthma symptoms. Na-Tosyl-Phe chloromethyl ketone (TPCK) is a chymotrypsine-like chymase inhibitor, which has anti-inflammatory properties. In this study, we investigated the effects of TPCK on mast cell synergistic degranulation induced by antigen and adenosine. Here, we report that TPCK almost completely suppressed enhanced degranulation by inhibiting granule movement. Consistent with this, intraperitoneal administration of TPCK resulted in significant amelioration of passive cutaneous anaphylaxis in mice. Furthermore, we demonstrated that TPCK completely inhibited Thr308 phosphorylation of protein kinase B in mast cells stimulated with antigen and adenosine. These results provide a novel action of TPCK for the prevention of mast cell degranulation induced by antigen and adenosine. (キーワード) Adenosine / Anaphylaxis / Animals / Antigens / Cell Degranulation / Cells, Cultured / Chymases / Mast Cells / Mice / Secretory Vesicles / Serine Proteinase Inhibitors / Tosylphenylalanyl Chloromethyl Ketone / Vasodilator Agents (出版サイトへのリンク) ● Publication site (DOI): 10.1016/j.lfs.2008.06.015 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 18634805 ● Search Scopus @ Elsevier (PMID): 18634805 ● Search Scopus @ Elsevier (DOI): 10.1016/j.lfs.2008.06.015 (DOI: 10.1016/j.lfs.2008.06.015, PubMed: 18634805)
31.	Toshio Inoue, Yoshihiro Suzuki, Tetsuro Yoshimaru and Chisei Ra : Nitric oxide protects mast cells from activation-induced cell death: the role of the phosphatidylinositol-3 kinase-Akt-endothelial nitric oxide synthase pathway., Journal of Leukocyte Biology, Vol.83, No.5, 1218-1229, 2008. (要約) NO is known to suppress mast cell activation, but the role of NO in mast cell survival is unclear. Ligation of the high-affinity receptor for IgE (FcepsilonRI) resulted in NO production in mast cells within minutes. This NO production was largely dependent on NO synthase (NOS) activity and extracellular Ca(2+). The NO production required an aggregation of FcepsilonRI and was accompanied by increased phosphorylation of endothelial NOS (eNOS) at Ser1177 and Akt at Ser473. The phosphorylation of eNOS and Akt and the production of NO were abolished by the PI-3K inhibitor wortmannin. Although thapsigargin (TG) induced NO production as well, this response occurred with a considerable lag time (>10 min) and was independent of FcepsilonRI aggregation and PI-3K and NOS activity. Mast cells underwent apoptosis in response to TG but not upon FcepsilonRI ligation. However, when the NOS-dependent NO production was blocked, FcepsilonRI ligation caused sizable apoptosis, substantial mitochondrial cytochrome c release, caspase-3/7 activation, and collapse of the mitochondrial membrane potential, all of which were inhibited by the caspase-3 inhibitor z-Asp-Glu-Val-Asp-fluoromethylketone. The data suggest that the NO produced by the PI-3K-Akt-eNOS pathway is involved in protecting mast cells from cell death. (キーワード) 1-Phosphatidylinositol 3-Kinase / Animals / Cell Death / Cell Line, Tumor / Cell Survival / Leukemia, Basophilic, Acute / Mast Cells / ミトコンドリア (mitochondria) / Nitric Oxide / Nitric Oxide Synthase Type III / Proto-Oncogene Proteins c-akt / Rats (出版サイトへのリンク) ● Publication site (DOI): 10.1189/jlb.1007667 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 18285401 ● Search Scopus @ Elsevier (PMID): 18285401 ● Search Scopus @ Elsevier (DOI): 10.1189/jlb.1007667 (DOI: 10.1189/jlb.1007667, PubMed: 18285401)
32.	Yoshihiro Suzuki, Toshio Inoue, Tetsuro Yoshimaru and Chisei Ra : Galectin-3 but not galectin-1 induces mast cell death by oxidative stress and mitochondrial permeability transition., Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, Vol.1783, No.5, 924-934, 2008. (要約) Galectin-1 and galectin-3 are the most ubiquitously expressed members of the galectin family and more importantly, these two molecules are shown to have opposite effects on pro-inflammatory responses and/or apoptosis depending on the cell type. Herein, we demonstrate for the first time that galectin-3 induces mast cell apoptosis. Mast cells expressed substantial levels of galectin-3 and galectin-1 and to a lesser extent the receptor for advanced glycation end products (RAGE) on their surfaces. Treatment of cells with galectin-3 at concentrations of > or =100 nM for 18-44 h resulted in cell death by apoptosis. Galectin-3-induced apoptosis was completely prevented by lactose, neutralizing antibody to RAGE, and the caspase-3 inhibitor z-DEVD-fmk. Galectin-3-induced apoptosis was also completely abolished by dithiothreitol and superoxide dismutase, but not inhibited by catalase. Moreover, galectin-3 but not galectin-1 induced the release of superoxide, which was blocked by lactose, anti-RAGE, and dithiothreitol. Finally, galectin-3-induced apoptosis was blocked by bongkrekic acid, an antagonist of the mitochondrial permeability transition pore (PTP), while atractyloside, an agonist of the PTP, greatly facilitated galectin-1-induced apoptosis. These data suggest that galectin-3 induces oxidative stress, PTP opening, and the caspase-dependent death pathway by binding to putative surface receptors including RAGE via the carbohydrate recognition domain. (キーワード) Animals / Apoptosis / Cell Line / Cells, Cultured / Galectin 1 / Galectin 3 / Lactose / Mast Cells / Mice / Mitochondria / Mitochondrial Membrane Transport Proteins / Oxidation-Reduction / Oxidative Stress / Receptors, Immunologic / Sulfhydryl Compounds (出版サイトへのリンク) ● Publication site (DOI): 10.1016/j.bbamcr.2008.01.025 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 18302939 ● Search Scopus @ Elsevier (PMID): 18302939 ● Search Scopus @ Elsevier (DOI): 10.1016/j.bbamcr.2008.01.025 (DOI: 10.1016/j.bbamcr.2008.01.025, PubMed: 18302939)
33.	Yoshihiro Suzuki, Tetsuro Yoshimaru, Toshio Inoue, Satoshi Nunomura and Chisei Ra : The high-affinity immunoglobulin E receptor (FcepsilonRI) regulates mitochondrial calcium uptake and a dihydropyridine receptor-mediated calcium influx in mast cells: Role of the FcepsilonRIbeta chain immunoreceptor tyrosine-based activation motif., Biochemical Pharmacology, Vol.75, No.7, 1492-1503, 2007. (要約) A growing body of evidence suggests that mitochondria take up calcium upon receptor (agonist) stimulation and that this contributes to the dynamics of spatiotemporal calcium signaling. We have previously shown that engagement of the high-affinity receptor for immunoglobulin E (FcepsilonRI) stimulates mitochondrial calcium ([Ca2+]m) uptake in mast cells. The present study was undertaken to investigate the mechanisms and biological significance of FcepsilonRI regulation of [Ca2+]m. Antigen stimulated [Ca2+]m uptake in a dose-dependent manner with a minimal effective dose of 0.03-3 ng/ml. This [Ca2+]m uptake took place immediately, reaching its peak within minutes and was inhibited by the src family kinase inhibitor PP1 and phosphatidylinositol-3-kinase inhibitor wortmannin. Analyses using mast cells expressing the wild-type or the mutated type of the FcepsilonRIbeta immunoreceptor tyrosine-based activation motif (ITAM) in which all tyrosine residues were replaced by phenylalanine revealed that the FcepsilonRIbeta ITAM is essential for a sustained [Ca2+]m uptake. The FcepsilonRIbeta ITAM was essential for overall calcium response upon weak FcepsilonRI stimulation (at low antigen concentration), while upon strong stimulation (at high antigen concentration) it appeared necessary selectively to an immediate calcium response that was sensitive to the dihydropyridine receptor (DHPR) antagonist nifedipine and wortmannin but not to the store-operated calcium entry (SOCE) antagonists such as 2-aminoethoxyphenyl borate and SK&F96365. These data demonstrate that the FcepsilonRIbeta regulates [Ca2+]m uptake in mast cells via the ITAM and suggest that this plays a key role in regulating calcium influx especially that induced via a DHPR-mediated calcium channel. (キーワード) Adaptor Proteins, Signal Transducing / Amino Acid Motifs / Animals / Calcium / Calcium Channels, L-Type / Cattle / Cell Line / Cells, Cultured / Enzyme Activation / Mast Cells / Membrane Proteins / Mice / Mice, Mutant Strains / Mitochondria / Receptors, IgE (出版サイトへのリンク) ● Publication site (DOI): 10.1016/j.bcp.2007.12.006 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 18243160 ● Search Scopus @ Elsevier (PMID): 18243160 ● Search Scopus @ Elsevier (DOI): 10.1016/j.bcp.2007.12.006 (DOI: 10.1016/j.bcp.2007.12.006, PubMed: 18243160)
34.	Toshio Inoue, Yoshihiro Suzuki, Tetsuro Yoshimaru and Chisei Ra : Reactive oxygen species produced up- or downstream of calcium influx regulate proinflammatory mediator release from mast cells: role of NADPH oxidase and mitochondria., Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, Vol.1783, No.5, 789-802, 2007. (要約) Earlier studies have demonstrated that mast cells produce reactive oxygen species (ROS), which play a role in regulating Ca(2+) influx, while in other cell types ROS are produced in a Ca(2+)-dependent manner. We sought to determine whether ROS are produced downstream of the extracellular Ca(2+) entry in mast cells. Thapsigargin (TG), a receptor-independent agonist, could evoke a robust burst of intracellular ROS. However, this response was distinct from the antigen-induced burst of ROS with respect to time course and dependence on Ca(2+) and phosphatidylinositol-3-kinase (PI3K). The antigen-induced ROS generation occurred immediately, while the TG-induced ROS generation occurred with a significant lag time (~2 min). Antigen but not TG caused extracellular release of superoxide (O(2)(-))/hydrogen peroxide (H(2)O(2)), which was blocked by diphenyleneiodonium, apocynin, and wortmannin. A capacitative Ca(2+) entry resulted in the generation of O(2)(-) in the mitochondria in a PI3K-independent manner. Blockade of ROS generation inhibited TG-induced mediator release. Finally, when used together, antigen and TG evoked the release of leukotriene C(4), tumor necrosis factor-alpha, and interleukin-13 as well as ROS generation synergistically. These results suggest that ROS produced upstream of Ca(2+) influx by NADPH oxidase and downstream of Ca(2+) influx by the mitochondria regulate the proinflammatory response of mast cells. (キーワード) 1-Phosphatidylinositol 3-Kinase / Animals / Antigens / Calcium / Cell Line / Cells, Cultured / Hydrogen Peroxide / Inflammation Mediators / Mast Cells / Mice / Mitochondria / NADPH Oxidase / Reactive Oxygen Species / Superoxides / Thapsigargin (出版サイトへのリンク) ● Publication site (DOI): 10.1016/j.bbamcr.2007.12.004 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 18178162 ● Search Scopus @ Elsevier (PMID): 18178162 ● Search Scopus @ Elsevier (DOI): 10.1016/j.bbamcr.2007.12.004 (DOI: 10.1016/j.bbamcr.2007.12.004, PubMed: 18178162)
35.	Tetsuro Yoshimaru, Yoshihiro Suzuki, Toshio Inoue, Osamu Niide and Chisei Ra : Silver activates mast cells through reactive oxygen species production and a thiol-sensitive store-independent Ca2+ influx., Free Radical Biology and Medicine, Vol.40, No.11, 1949-1959, 2006. (要約) In genetically susceptible human and/or experimental animals, heavy metals such as mercury, gold, and silver have been shown to highly induce adverse immunological reactions such as allergy and autoimmunity, in which mast cell degranulation is implicated as playing a role. We previously reported that silver activates mast cells and induces Ca2+ influx without stimulating intracellular signaling events required for activation of store-operated Ca2+ channels (SOCs). The purpose of the present study was to elucidate the possible involvement of reactive oxygen species (ROS) in the biological effects of silver. Analysis using oxidant-sensitive fluorescent probes such as dichlorodihydrofluorescein and scopoletin, as well as MCLA-amplified chemiluminescence, showed that silver induced intracellular production and/or extracellular release of ROS. Silver induced mast cell degranulation in a Ca2+ -dependent manner. Unlike IgE antigen, silver-induced Ca2+ influx was not affected by depletion of internal Ca2+ stores. Instead, the metal-induced Ca2+ influx was abolished and reversed by the cell-impermeant thiol-reducing agent dithiothreitol, indicating the regulation by oxidation of vicinal thiols on the cell surface. Consistent with this view, Ca2+ influx was blocked by the glutathione peroxidase mimetic ebselen (2-phenyl-1,2-benzisoselenazol-3(2H)-one) and the superoxide dismutase mimetic manganese(III) tetrakis 4-(benzoic acid)porphyrin, but not by exogenously added catalase or superoxide dismutase. These findings indicate that silver evokes the release of ROS and oxidation of thiols critical for the activation of a Ca2+ channel other than SOC. Such a novel ROS-dependent pathway might play a role in mast cell degranulation in metal-induced allergic and autoimmune reactions. (キーワード) 1-Phosphatidylinositol 3-Kinase / Animals / Calcium / Cell Degranulation / Enzyme Activation / Flow Cytometry / Ion Transport / Luminescence / Mast Cells / Mice / Mice, Inbred C57BL / Oxidation-Reduction / Reactive Oxygen Species / Silver / Sulfhydryl Compounds (出版サイトへのリンク) ● Publication site (DOI): 10.1016/j.freeradbiomed.2006.01.023 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 16716896 ● Search Scopus @ Elsevier (PMID): 16716896 ● Search Scopus @ Elsevier (DOI): 10.1016/j.freeradbiomed.2006.01.023 (DOI: 10.1016/j.freeradbiomed.2006.01.023, PubMed: 16716896)
36.	Yoshihiro Suzuki, Tetsuro Yoshimaru, Toshio Inoue and Chisei Ra : Mitochondrial Ca2+ flux is a critical determinant of the Ca2+ dependence of mast cell degranulation., Journal of Leukocyte Biology, Vol.79, No.3, 508-518, 2005. (要約) An increase in intracellular Ca2+ ([Ca2+]i) is necessary for mast cell exocytosis, but there is controversy over the requirement for Ca2+ in the extracellular medium. Here, we demonstrate that mitochondrial function is a critical determinant of Ca2+ dependence. In the presence of extracellular Ca2+, mitochondrial metabolic inhibitors, including rotenone, antimycin A, and the protonophore carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP), significantly reduced degranulation induced by immunoglobulin E (IgE) antigen or by thapsigargin, as measured by beta-hexosaminidase release. In the absence of extracellular Ca2+; however, antimycin A and FCCP, but not rotenone, enhanced, rather than reduced, degranulation to a maximum of 76% of that observed in the presence of extracellular Ca2+. This enhancement of extracellular, Ca2+-independent degranulation was concomitant with a rapid collapse of the mitochondrial transmembrane potential. Mitochondrial depolarization did not enhance degranulation induced by thapsigargin, irrespective of the presence or absence of extracellular Ca2+. IgE antigen was more effective than thapsigargin as an inducer of [Ca2+]i release, and mitochondrial depolarization augmented IgE-mediated but not thapsigargin-induced Ca2+ store release and mitochondrial Ca2+ ([Ca2+]m) release. Finally, atractyloside and bongkrekic acid [an agonist and an antagonist, respectively, of the mitochondrial permeability transition pore (mPTP)], respectively, augmented and reduced IgE-mediated Ca2+ store release, [Ca2+]m release, and/or degranulation, whereas they had no effects on thapsigargin-induced Ca2+ store release. These data suggest that the mPTP is involved in the regulation of Ca2+ signaling, thereby affecting the mode of mast cell degranulation. This finding may shed light on a new role for mitochondria in the regulation of mast cell activation. (キーワード) Animals / Antimycin A / Atractyloside / Bongkrekic Acid / Calcium / Calcium Signaling / Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone / Cell Degranulation / Cell Line, Tumor / Cytoplasmic Granules / Energy Metabolism / Enzyme Inhibitors / Extracellular Fluid / Immunoglobulin E / Ion Channels / Mast Cells / Membrane Potentials / Mice / Mice, Inbred C57BL / Mitochondria / Mitochondrial Membrane Transport Proteins / Rats / Rotenone / Thapsigargin / beta-N-Acetylhexosaminidases (出版サイトへのリンク) ● Publication site (DOI): 10.1189/jlb.0705412 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 16365155 ● Search Scopus @ Elsevier (PMID): 16365155 ● Search Scopus @ Elsevier (DOI): 10.1189/jlb.0705412 (DOI: 10.1189/jlb.0705412, PubMed: 16365155)
37.	Osamu Niide, Yoshihiro Suzuki, Tetsuro Yoshimaru, Toshio Inoue, Tadatoshi Takayama and Chisei Ra : Fungal metabolite gliotoxin blocks mast cell activation by a calcium- and superoxide-dependent mechanism: implications for immunosuppressive activities., Clinical Immunology, Vol.118, No.1, 108-116, 2005. (要約) Fungal secondary metabolites such as gliotoxin, an epipolythiodioxopiperazine toxin produced by pathogenic fungi like Candida and Aspergillus, possess immunosuppressive activities and have been thought to contribute to pathology of fungal infections in animals and humans. Since recent studies show that mast cell plays a crucial role in the front of host defense, we examined whether fungal secondary metabolites affected mast cell activation. We found that gliotoxin had suppressive effects on FcepsilonRI-dependent or -independent mast cell activation, including degranulation, leukotriene C4 secretion, and TNF-alpha and IL-13 production. Gliotoxin also suppressed intracellular Ca2+ rise through store-operated Ca2+ channels with a minimal effect on depletion of internal Ca2+ stores. Finally, gliotoxin induced intracellular production of superoxide possibly through a thiol redox cycling, which appeared to mediate suppressive effects on mast cell activation. These findings suggest that suppression of mast cell activation might contribute to the establishment of infections with gliotoxin-producing fungi. (キーワード) Animals / Calcium / Calcium Signaling / Cell Degranulation / Cells, Cultured / Gliotoxin / Histamine Release / Immunosuppressive Agents / Interleukin-13 / Leukotriene C4 / Mast Cells / Mice / Mice, Inbred C57BL / Molecular Structure / Receptors, IgE / Superoxides / Tumor Necrosis Factor-alpha (出版サイトへのリンク) ● Publication site (DOI): 10.1016/j.clim.2005.08.012 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 16213796 ● Search Scopus @ Elsevier (PMID): 16213796 ● Search Scopus @ Elsevier (DOI): 10.1016/j.clim.2005.08.012 (DOI: 10.1016/j.clim.2005.08.012, PubMed: 16213796)
38.	Satoshi Nunomura, Yasuhiro Gon, Tetsuro Yoshimaru, Yoshihiro Suzuki, Hajime Nishimoto, Toshiaki Kawakami and Chisei Ra : Role of the FcepsilonRI beta-chain ITAM as a signal regulator for mast cell activation with monomeric IgE., International Immunology, Vol.17, No.6, 685-694, 2005. (要約) The beta-chain of the high-affinity receptor for IgE (FcepsilonRI) plays a crucial role for amplification of the intracellular signaling in mast cells upon FcepsilonRI cross-linking by IgEantigen complexes (IgEAg). Some monomeric IgE as well as IgE*Ag stimulate FcepsilonRI-signaling pathways, leading to cell activation, whereas the biological functions of the beta-chain in the monomeric IgE-mediated mast cell signaling and responses are largely unknown. In the present study, FcepsilonRI is reconstituted with either wild-type beta-chain or mutated beta-chain immunoreceptor tyrosine-based activation motif (ITAM) employing retrovirus-mediated gene transfer into the FcepsilonRI beta-chain-/- mast cells. We demonstrated that the transfectants with mutated beta-chain ITAM stimulated with monomeric IgE sufficiently produce inflammatory cytokines, although degranulation, intracellular Ca(2+) mobilization and leukotriene C(4) synthesis are significantly reduced. Furthermore, analyses of molecular mechanisms of the signaling revealed that the expression of cytokine genes and activation of extracellular signal-regulated kinase 1/2 and protein kinase C were significantly delayed in the beta-chain ITAM mutant cells stimulated with monomeric IgE, suggesting that the beta-chain ITAM regulates kinetics of gene transcriptions and signaling pathways for cytokine production. These findings for the first time revealed the unique functions of the beta-chain ITAM in both chemical mediator release and cytokine production of mast cells upon monomeric IgE stimulation. (キーワード) Animals / Calcium / Cells, Cultured / Cytokines / Extracellular Signal-Regulated MAP Kinases / Immunoglobulin E / Immunoglobulin epsilon-Chains / Leukotriene C4 / Mast Cells / Mice / Mice, Knockout / Protein Kinase C / Receptors, IgE / Signal Transduction / Transfection / beta-N-Acetylhexosaminidases / src-Family Kinases (出版サイトへのリンク) ● Publication site (DOI): 10.1093/intimm/dxh248 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 15944196 ● Search Scopus @ Elsevier (PMID): 15944196 ● Search Scopus @ Elsevier (DOI): 10.1093/intimm/dxh248 (DOI: 10.1093/intimm/dxh248, PubMed: 15944196)
39.	T Suda, Y Suzuki, T Matsui, T Inoue, O Niide, Tetsuro Yoshimaru, H Suzuki, C Ra and T Ochiai : Dapsone suppresses human neutrophil superoxide production and elastase release in a calcium-dependent manner., The British Journal of Dermatology, Vol.152, No.5, 887-895, 2005. (要約) BACKGROUND: Dapsone (4,4'-diaminodiphenyl sulphone) is a powerful therapeutic tool in many skin diseases including neutrophilic dermatoses. The drug has an outstanding therapeutic efficacy against many skin diseases characterized by neutrophil-rich infiltrates; however, mechanisms of its action are poorly understood. OBJECTIVES: We investigated the effects of dapsone on respiratory and secretory functions of human neutrophils triggered by the chemotactic peptide N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP), the physiological agonist C5a, and phorbol myristate acetate (PMA). METHODS: Human neutrophils were isolated from venous blood obtained from healthy donors. We detected extracellular production of superoxide (O(2) (-)) by cytochrome C reduction assay, and intracellular production of O(2) (-) by flow cytometry. Neutrophil elastase release was measured by the cleavage of the specific elastase substrate N-methoxysuccinyl-Ala-Ala-Pro-Val-p-nitroanilide. Measurement of cytosolic free calcium concentration was performed using the calcium-reactive fluorescence probe, Fluo-3. RESULTS: Dapsone suppressed intra- and extracellular production of O(2) (-) and elastase release triggered by fMLP and C5a, but not by PMA. Both fMLP and C5a signalled the above pathways by inducing calcium influx, but PMA functions bypassed calcium influx. Dapsone was capable of antagonizing the induction of calcium influx. CONCLUSIONS: These findings suggest that one mechanism of the anti-inflammatory action of dapsone is inhibition of calcium-dependent functions of neutrophils including release of tissue-damaging oxidants and proteases in the affected skin. (キーワード) Anti-Inflammatory Agents, Non-Steroidal / Calcium / Cells, Cultured / Complement C5a / Dapsone / Dose-Response Relationship, Drug / Humans / N-Formylmethionine Leucyl-Phenylalanine / Neutrophil Activation / Neutrophils / Pancreatic Elastase / Respiratory Burst / Superoxides / Tetradecanoylphorbol Acetate (出版サイトへのリンク) ● Publication site (DOI): 10.1111/j.1365-2133.2005.06559.x (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 15888142 ● Search Scopus @ Elsevier (PMID): 15888142 ● Search Scopus @ Elsevier (DOI): 10.1111/j.1365-2133.2005.06559.x (DOI: 10.1111/j.1365-2133.2005.06559.x, PubMed: 15888142)
40.	Yoshihiro Suzuki, Tetsuro Yoshimaru, Takashi Matsui, Toshio Inoue, Osamu Niide, Satoshi Nunomura and Chisei Ra : Fc epsilon RI signaling of mast cells activates intracellular production of hydrogen peroxide: role in the regulation of calcium signals., The Journal of Immunology, Vol.171, No.11, 6119-6127, 2003. (要約) Earlier studies, including our own, revealed that activation of mast cells is accompanied by production of reactive oxygen species (ROS) that help to mediate the release of the inflammatory mediators, including histamine and eicosanoids. However, little is known about the mechanisms of ROS production, including the species of oxidants produced. In this study we show that in both the RBL-2H3 mast cell line and bone marrow-derived mast cells, FcepsilonRI cross-linking stimulates intracellular oxidative burst, including hydrogen peroxide (H(2)O(2)) production, as defined with the oxidant-sensitive dyes dichlorofluorescein and scopoletin and the selective scavenger ebselen (2-phenyl-1,2-benzisoselenazol-3(2H)-one). The oxidative burst was observed immediately after stimulation and was most likely due to an NAD(P)H oxidase. Experiments using selective pharmacological inhibitors demonstrated that activation of tyrosine kinases and phosphatidylinositol-3-kinase is required for induction of the oxidative burst. Blockade of the oxidative burst by diphenyleneiodonium impaired the release of preformed granular mediators, such as histamine and beta-hexosaminidase, and the secretion of newly synthesized leukotriene C(4), whereas selective scavenging H(2)O(2) by ebselen impaired leukotriene C(4) secretion, but not degranulation. Sustained elevation of cytosolic calcium through store-operated calcium entry was totally abolished when ROS production was blocked. In contrast, selective depletion of H(2)O(2) caused a considerable decrease and delay of the calcium response. Finally, tyrosine phosphorylation of phospholipase Cgamma and the linker for activation of T cells, an event required for calcium influx, was suppressed by diphenyleneiodonium and ebselen. These studies demonstrate that activation of the intracellular oxidative burst is an important regulatory mechanism of mast cell responses. (キーワード) 1-Phosphatidylinositol 3-Kinase / Adaptor Proteins, Signal Transducing / Animals / Antioxidants / Calcium / Calcium Signaling / Carrier Proteins / Cell Line, Tumor / Hydrogen Peroxide / Intracellular Fluid / Mast Cells / Membrane Proteins / Mice / NADH, NADPH Oxidoreductases / NADPH Oxidase / Onium Compounds / Phospholipase C gamma / Phosphoproteins / Phosphorylation / Phosphotyrosine / Protein-Tyrosine Kinases / Rats / Reactive Oxygen Species / Receptors, IgE / Respiratory Burst / T-Lymphocytes / Type C Phospholipases (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 14634127 ● Search Scopus @ Elsevier (PMID): 14634127 (PubMed: 14634127)
41.	Yoshihiro Suzuki, Tetsuro Yoshimaru, Takashi Matsui and Chisei Ra : Silver activates calcium signals in rat basophilic leukemia-2H3 mast cells by a mechanism that differs from the Fc epsilon RI-activated response., The Journal of Immunology, Vol.169, No.7, 3954-3962, 2002. (要約) We previously showed that silver stimulates degranulation and leukotriene (LT) C(4) production in rat basophilic leukemia mast cells and now show that silver induces these events by a mechanism that differs from the FcepsilonRI-mediated response. In common with FcepsilonRI cross-linking, silver induced tyrosine phosphorylation of extracellular signal-regulated kinases and furthermore, PD98059, a specific inhibitor of extracellular signal-regulated kinase kinase dose-dependently inhibited the silver-induced LTC(4) production. In contrast to FcepsilonRI cross-linking, silver had no effect on the production of IL-4 and TNF-alpha, indicating that different mechanisms are involved in the activation by these two stimuli. In line with this, silver had no or only marginal effect on the tyrosine phosphorylation of FcepsilonRIbeta, Lyn, Syk, and linker for activation of T cells, the early and crucial events in FcepsilonRI signaling. Silver induced calcium signals that were involved in the metal-induced degranulation, but not LTC(4) production. Unlike Ag, the silver-induced calcium signals were resistant to the depletion of thapsigargin-sensitive calcium stores and the inhibition of tyrosine kinases and phospholipase Cgamma. These findings indicate that silver activates mast cells by bypassing the early signaling events required for the induction of calcium influx. Our data strongly suggest the existence of an alternative pathway bypassing the early signaling events in mast cell activation and indicate that silver may be useful for analyses of such alternative mechanisms. (キーワード) Animals / Calcium / Calcium Signaling / Carrier Proteins / Cell Degranulation / Enzyme Precursors / Immunity, Innate / Interleukin-4 / Intracellular Signaling Peptides and Proteins / Isoenzymes / Leukemia, Basophilic, Acute / Leukotriene C4 / Mast Cells / Mitogen-Activated Protein Kinases / Phospholipase C gamma / Phosphoproteins / Protein-Tyrosine Kinases / Rats / Receptors, IgE / Silver / Silver Nitrate / Thapsigargin / Tumor Cells, Cultured / Tumor Necrosis Factor-alpha / Type C Phospholipases / Tyrosine / src-Family Kinases (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 12244196 ● Search Scopus @ Elsevier (PMID): 12244196 (PubMed: 12244196)
42.	Tetsuro Yoshimaru, Y Suzuki, T Matsui, K Yamashita, T Ochiai, M Yamaki and K Shimizu : Blockade of superoxide generation prevents high-affinity immunoglobulin E receptor-mediated release of allergic mediators by rat mast cell line and human basophils., Clinical and Experimental Allergy, Vol.32, No.4, 612-618, 2002. (要約) BACKGROUND: Previous studies have shown that rat peritoneal mast cells and mast cell model rat basophilic leukaemia (RBL-2H3) cells generate intracellular reactive oxygen species (ROS) in response to antigen challenge. However, the physiological significance of the burst of ROS is poorly understood. OBJECTIVE: The present study was undertaken to investigate the role of superoxide anion in mediator release in rat and human cell systems. METHODS: RBL-2H3 cells were directly stimulated with anti-rat FcepsilonRI alpha-subunit monoclonal antibody (mAb). For the analysis of human cell system, leucocytes were isolated by dextran sedimentation from healthy volunteers or from patients, and challenged either with anti-human FcepsilonRI mAb or with the relevant antigens. Superoxide generation was determined by chemiluminescence-based methods. The releases of histamine and leukotrienes (LT)s were determined by enzyme-linked immunosorben assay (ELISA). RESULTS: Cross-linking of FcepsilonRI on RBL-2H3 cells or on human leucocytes from healthy donors by the anti-FcepsilonRI mAb resulted in a rapid generation of superoxide anion, as determined by chemiluminescence using superoxide-specific probes. Similarly, leucocytes from patients generated superoxide anion in response to the challenge with the relevant allergen but not with the irrelevant allergen. Furthermore, diphenyleneiodonium (DPI), a well-known inhibitor of flavoenzymes suppressed the superoxide generation and the release of histamine and LTC4 induced by the anti-FcepsilonRI mAb or by allergen in parallel. CONCLUSION: These results indicate that both RBL-2H3 cells and human basophils generate superoxide anion upon FcepsilonRI cross-linking either by antibody or by allergen challenge and that blockade of the generation prevents the release of allergic mediators. The findings strongly support the role of superoxide generation in the activation of mast cells and basophils under both physiological and pathological conditions. The findings suggest that drugs regulating the superoxide generation have potential therapeutic use for allergic disorders. (キーワード) Adult / Animals / Basophils / Cell Degranulation / Cell Line / Female / Histamine Release / Humans / Hypersensitivity, Immediate / Kinetics / Leukotrienes / Male / Mast Cells / Middle Aged / Onium Compounds / Rats / Receptors, IgE / Superoxides (出版サイトへのリンク) ● Publication site (DOI): 10.1046/j.0954-7894.2002.01263.x (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 11972610 ● Search Scopus @ Elsevier (PMID): 11972610 ● Search Scopus @ Elsevier (DOI): 10.1046/j.0954-7894.2002.01263.x (DOI: 10.1046/j.0954-7894.2002.01263.x, PubMed: 11972610)
43.	Y Suzuki, Tetsuro Yoshimaru, K Yamashita, T Matsui, M Yamaki and K Shimizu : Exposure of RBL-2H3 mast cells to Ag(+) induces cell degranulation and mediator release., Biochemical and Biophysical Research Communications, Vol.283, No.3, 707-714, 2001. (要約) There is a growing need to understand the impact of environmental sulfhydryl group-reactive heavy metals on the immune system. Here we show that Ag(+) induces mast cell degranulation, as does the aggregation of the high affinity immunoglobulin E receptor (FcepsilonRI). Micromolar quantities of Ag(+) specifically induced degranulation of mast cell model rat basophilic leukemia (RBL-2H3) cells without showing cytotoxicity. The Ag(+)-mediated degranulation could be observed as rapidly as 5 min after the addition of the ions. Ag(+) also induced a rapid change in tyrosine phosphorylation of multiple cellular proteins including the focal adhesion kinase but not Syk kinase. The Syk-selective inhibitor piceatannol and the Src family-selective tyrosine kinase inhibitor PP1 dose-dependently inhibited FcepsilonRI-mediated degranulation, whereas neither compound inhibited the Ag(+)-mediated degranulation. Furthermore, likewise FcepsilonRI aggregation, Ag(+) also induced leukotriene secretion. These results show that Ag(+) activates RBL-2H3 mast cells through a tyrosine phosphorylation-linked mechanism, which is distinct from that involved in FcepsilonRI-mediated activation. (キーワード) Animals / Cell Degranulation / Cell Line / Enzyme Inhibitors / Enzyme Precursors / Focal Adhesion Kinase 1 / Focal Adhesion Protein-Tyrosine Kinases / Histamine Release / Intracellular Signaling Peptides and Proteins / Leukotrienes / Mast Cells / Mercury / Phosphorylation / Protein-Tyrosine Kinases / Proteins / Rats / Receptors, IgE / Silver / Tyrosine (出版サイトへのリンク) ● Publication site (DOI): 10.1006/bbrc.2001.4844 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 11341783 ● Search Scopus @ Elsevier (PMID): 11341783 ● Search Scopus @ Elsevier (DOI): 10.1006/bbrc.2001.4844 (DOI: 10.1006/bbrc.2001.4844, PubMed: 11341783)
44.	T Matsui, Y Suzuki, K Yamashita, Tetsuro Yoshimaru, M Suzuki-Karasaki, S Hayakawa, M Yamaki and K Shimizu : Diphenyleneiodonium prevents reactive oxygen species generation, tyrosine phosphorylation, and histamine release in RBL-2H3 mast cells., Biochemical and Biophysical Research Communications, Vol.276, No.2, 742-748, 2000. (要約) Mast cells play a central role in immediate allergic reactions mediated by immunoglobulin E. It has recently been reported that mast cells generate intracellular reactive oxygen species (ROS) in response to stimulation with divergent physiologically relevant stimulants. However, the physiological role of ROS is poorly understood. Here we demonstrate that mast cell model rat basophilic leukemia (RBL-2H3) cells generate ROS in response to antigen and the calcium-ionophore A23187 via activation of diphenyleneiodonuim (DPI)-sensitive enzyme and that blockade of ROS generation by DPI suppresses histamine release induced by either stimulant. Increased tyrosine phosphorylation of pp125(FAK) and a 77-kDa protein coprecipitating specifically with the kinase occurred in parallel with the secretion, and blockade of ROS generation by DPI also suppressed the tyrosine phosphorylation of both proteins. These findings suggest that ROS generated by a flavoenzyme-dependent mechanism may be involved in histamine release through the pp125(FAK) pathway. (キーワード) Animals / Calcimycin / Enzyme Inhibitors / Focal Adhesion Kinase 1 / Focal Adhesion Protein-Tyrosine Kinases / Histamine / Histamine Release / Mast Cells / Molecular Weight / Onium Compounds / Phosphorylation / Protein-Tyrosine Kinases / Rats / Reactive Oxygen Species / Receptors, IgE / Tumor Cells, Cultured / Tyrosine (出版サイトへのリンク) ● Publication site (DOI): 10.1006/bbrc.2000.3545 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 11027541 ● Search Scopus @ Elsevier (PMID): 11027541 ● Search Scopus @ Elsevier (DOI): 10.1006/bbrc.2000.3545 (DOI: 10.1006/bbrc.2000.3545, PubMed: 11027541)
45.	K Yamashita, Y Suzuki, T Matsui, Tetsuro Yoshimaru, M Yamaki, M Suzuki-Karasaki, S Hayakawa and K Shimizu : Epigallocatechin gallate inhibits histamine release from rat basophilic leukemia (RBL-2H3) cells: role of tyrosine phosphorylation pathway., Biochemical and Biophysical Research Communications, Vol.274, No.3, 603-608, 2000. (要約) Some tea polyphenolic compounds including (-)-epigallocatechin gallate (EGCG) have been shown to inhibit histamine release from mast cells through poorly understood mechanisms. By using a mast cell model rat basophilic leukemia (RBL-2H3) cells we explored the mechanism of the inhibition. EGCG inhibited histamine release from RBL-2H3 cells in response to antigen or the calcium-ionophore A23187, while (-)-epicatechin (EC) had little effect. Increased tyrosine phosphorylation of several proteins including approximately 120 kDa proteins occurred in parallel with the secretion induced by either stimulation. EGCG also inhibited tyrosine phosphorylation of the approximately 120-kDa proteins induced by either stimulation, whereas EC did not. The tyrosine kinase-specific inhibitor piceatannol inhibited the secretion and tyrosine phosphorylation of these proteins induced by either stimulation also. Further analysis showed that the focal adhesion kinase pp125(FAK) was one of the approximately 120-kDa proteins. These findings suggest that EGCG prevents histamine release from mast cells mainly by inhibiting tyrosine phosphorylation of proteins including pp125(FAK). (キーワード) Animals / Antineoplastic Agents / カテキン (catechin) / Histamine Release / Leukemia, Basophilic, Acute / Leukemia, Experimental / Mast Cells / リン酸化 (phosphorylation) / Rats / シグナル伝達 (signal transduction) / Tumor Cells, Cultured / Tyrosine (出版サイトへのリンク) ● Publication site (DOI): 10.1006/bbrc.2000.3200 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 10924324 ● Search Scopus @ Elsevier (PMID): 10924324 ● Search Scopus @ Elsevier (DOI): 10.1006/bbrc.2000.3200 (DOI: 10.1006/bbrc.2000.3200, PubMed: 10924324)

学術論文(紀要・その他):

1.	Daishiroh Kobayashi, Masaya Denda, JUNYA Hayashi, Kohta Hidaka, Yutaka Kohmura, Takaaki Tsunematsu, Kohei Nishino, Harunori Yoshikawa, OHKAWACHI Kento, Kiyomi Nigorikawa, Tetsuro Yoshimaru, Naozumi Ishimaru, Nomura Wataru, Toyomasa Katagiri, Hidetaka Kosako and Akira Otaka : Sulfoxide-mediated Cys-Trp-selective bioconjugation that enables protein labeling and peptide heterodimerization, ChemRxiv, 2024. (出版サイトへのリンク) ● Publication site (DOI): 10.26434/chemrxiv-2024-tkv7w-v2 (文献検索サイトへのリンク) ● Search Scopus @ Elsevier (DOI): 10.26434/chemrxiv-2024-tkv7w-v2 (DOI: 10.26434/chemrxiv-2024-tkv7w-v2)
2.	Keitaroh Anyohji, Keisuke Aihara, Tetsuro Yoshimaru, Akira Shigenaga, Toyomasa Katagiri and Akira Otaka : Development of anti-cancer peptide based on prohibitin 2, Peptide Science 2018, 46, 2019.

総説・解説:

1.	吉丸哲郎, 片桐豊雅 : 分子内架橋型BIG3-PHB2相互作用ペプチドによるホルモン依存性乳がんの新規治療法の開発, 最新医学, Vol.74, No.5, 115-121, 2019年. (キーワード) 乳癌 (breast cancer)
2.	吉丸哲郎, 松下洋輔, 片桐豊雅 : 包括的ゲノム解析を通じたトリプルネガティブ乳癌の分子特性, 乳癌の臨床, Vol.31, No.5, 377-385, 2016年10月.
3.	Yoshihiro Suzuki, Tetsuro Yoshimaru, Toshio Inoue, Osamu Niide and Chisei Ra : Role of oxidants in mast cell activation., Chemical Immunology and Allergy, Vol.87, 32-42, 2005. (要約) Reactive oxygen species (ROS), such as superoxide, hydrogen peroxide (H2O2), and hydroxyl radical, have for a long time been considered as accidental by-products of respiratory energy production in mitochondria and as being useless and rather deleterious to biological systems. Contrary to such a classical view, accumulating evidence indicates that upon stimulation of divergent receptor systems, ROS are intentionally produced and even required for appropriate signal transduction and biological responses. Work by our group and that of others have shown that stimulation of mast cells through the high-affinity IgE receptor (FcepsilonRI) induces the production of ROS such as superoxide and H2O2 possibly by the phagocyte NADPH oxidase homologue and that these endogenously produced oxidants have important functions in regulation of various mast cell responses, including degranulation, leukotriene secretion, and cytokine production. Subsequent studies have defined particular biochemical pathways that can be targeted by ROS and/or cellular redox balance. More recent research reveals that ROS may also play an important role in mast cell activation by divergent allergy-relevant environmental substances, for instance heavy metals and polycyclic aromatic hydrocarbons. This review summarizes current knowledge on the role of endogenous oxidants in mast cell activation. (キーワード) Animals / Basophils / Humans / Hypersensitivity / Mast Cells / Mice / Models, Immunological / NADPH Oxidase / Oxidants / Oxidation-Reduction / Reactive Oxygen Species / Receptors, IgE / Signal Transduction (出版サイトへのリンク) ● Publication site (DOI): 10.1159/000087569 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 16107761 ● Search Scopus @ Elsevier (PMID): 16107761 ● Search Scopus @ Elsevier (DOI): 10.1159/000087569 (DOI: 10.1159/000087569, PubMed: 16107761)

国際会議:

1.	Chiho Shinozaki, Yutaka Kohmura, Tetsuro Yoshimaru, Tsuyoshi Tahara, Masaya Denda, Hidefumi Mukai, Kohta Mohri, Yi Long Chen, Toyomasa Katagiri and Akira Otaka : Study on a lipidated anti-cancer peptide allowing long-lasting duration in mice model, AIMECS 2023, Seoul, Jun. 2023.
2.	Tetsuro Yoshimaru, Yosuke Matsushita, Sasa Mitsunori, Miyoshi Yasuo and Toyomasa Katagiri : BIG3 phosphatase inactivates tumor suppressor PHB2 via tis dephosphorylation to contribute to the breast carcinogenesis, The 14th International Conference on Protein Phosphatase, Online, Dec. 2020.
3.	Yosuke Matsushita, Masato Komatsu, Kazuma Kiyotani, Tetsuro Yoshimaru, Suzuki Hiromu, Miyoshi Yasuo, Sasa Mitsunori and Toyomasa Katagiri : Frequent downregulation of SALL3 by genetic and epigenetic alterations is involved in progression and chemoresistance of triple negative breast cancers, American Association for Cancer Research ANNUAL MEETING 2019, Atlanta, Apr. 2019.
4.	Tetsuro Yoshimaru, Yosuke Matsushita, Sasa Mitsunori, Miyoshi Yasuo and Toyomasa Katagiri : PHB2 inactivation by AKAP-BIG3 is required for progression of HER2-overexpressing breast cancer, American Association for Cancer Research ANNUAL MEETING 2019, Atlanta, Apr. 2019.
5.	Keitaroh Anyohji, Keisuke Aihara, Tetsuro Yoshimaru, Akira Shigenaga, Toyomasa Katagiri and Akira Otaka : Development of anti-cancer peptide based on prohibitin 2, 10th International Peptide Symposium, Kyoto, Dec. 2018.
6.	Yosuke Matsushita, Masato Komatsu, Kazuma Kiyotani, Tetsuro Yoshimaru, Suzuki Hiromu, Miyoshi Yasuo, Sasa Mitsunori and Toyomasa Katagiri : Frequent downregulation of SALL3 by recurrent genetic and epigenetic alterations is involved in triple-negative breast cancers, American Association for Cancer Research ANNUAL MEETING 2018, Vol.78, No.13, Chicago, Apr. 2018. (出版サイトへのリンク) ● Publication site (DOI): 10.1158/1538-7445.AM2018-5315 (文献検索サイトへのリンク) ● Search Scopus @ Elsevier (DOI): 10.1158/1538-7445.AM2018-5315 (DOI: 10.1158/1538-7445.AM2018-5315)
7.	Tetsuro Yoshimaru, Yosuke Matsushita, Sasa Mitsunori, Miyoshi Yasuo and Toyomasa Katagiri : Overcoming trastuzumab resistance in HER2-overexpressing breast cancer by utilizing PHB2, a tumor suppressor of multiple resistance pathways, American Association for Cancer Research ANNUAL MEETING 2018, Chicago, Apr. 2018.
8.	Toyomasa Katagiri, Kei Daizumoto, Tetsuro Yoshimaru, Yosuke Matsushita, Tomoya Fukawa, Ono Masaya and Hiro-omi Kanayama : DDX31 cooperates with mutant p53 and EGFR to promote the multistep progression of invasive bladder cancer, American Association For Cancer Research ANNUAL MEETING 2018, Chicago, Apr. 2018.
9.	Akira Otaka, Keisuke Aihara, Tetsuro Yoshimaru, Akira Shigenaga and Toyomasa Katagiri : Development of long-lasting stapled peptides targeting BIG3-PHB2 interaction in breast cancer cells, The 6th Pharmaceutical Sciences World Congress 2017, Stockholm, May 2017.
10.	Tetsuro Yoshimaru and Toyomasa Katagiri : Development of chemically modified peptide inhibitor ERAP targeting BIG3-PHB2 complex on hormone-resistant breast cancer, 2nd International Symposium of Molecular Medicine in Tokushima University, Tokushima, Nov. 2016.
11.	Tetsuro Yoshimaru, Ono Masaya, Mizuguchi Kenji, Miyoshi Yasuo, Mitsunori Sasa and Toyomasa Katagiri : A novel A-kinase anchoring protein BIG3, coordinates estrogen signalling in breast cancer cells, The 12th International Conference on Protein Phosphatase, Oct. 2016.
12.	Toyomasa Katagiri, Tetsuro Yoshimaru, Masato Komatsu and Taisuke Matsuo : BIG3-PHB2 Interaction is a key therapeutic target in Iuminal-type of breast cancer., Amerian Association for Cancer Research (AACR) Annal Meeting 2014, San Diego, Apr. 2014.
13.	Taisuke Matsuo, Ono Masaya, Tetsuro Yoshimaru, Miyoshi Yasuo, Sasa Mitsunori, Nakamura Yusuke and Toyomasa Katagiri : Functional roles of a novel glycosyltrasnferase BCGT1 in breast cancer cells, 70th Annual Meeting of the Japanese Cancer Association, Oct. 2011.
14.	Tetsuro Yoshimaru, Komatsu Masato, Taisuke Matsuo, Miyoshi Yasuo, Sasa Mitsunori, Nakamura Yusuke and Toyomasa Katagiri : Novel modeling of ER signaling regulation in E2-dependent breast cancer - New therapeutic target for ERAP1-REA complex, 70th Annual Meeting of the Japanese Cancer Association, Oct. 2011.
15.	片桐豊雅, 吉丸哲郎, 松尾泰佑, 三好康雄, 笹三徳, 中村祐輔 : 乳癌における新規エストロゲンシグナル活性化機構の解明および治療戦略, 第69回日本癌学会学術総会, 2010年9月.
16.	松尾泰佑, 吉丸哲郎, 三好康雄, 笹三徳, 中村祐輔, 片桐豊雅 : 新規乳癌治療標的分子BCGT1の同定とその機能解析, 第69回日本癌学会学術総会, 大阪, 2010年9月.
17.	吉丸哲郎, 松尾泰佑, 三好康雄, 笹三徳, 中村祐輔, 片桐豊雅 : 遺伝子発現解析によるトリプルネガティブ乳癌の分子機構の解明, 第69回日本癌学会学術総会, 大阪, 2010年9月.
18.	Toyomasa Katagiri, Tetsuro Yoshimaru, Taisuke Matsuo, Miyoshi Yasuo, Sasa Mitsunori and Nakamura Yusuke : Critical role of transactivation of ERAP1,estrogen receptor activity-regulated protein 1, in estrogen-dependent breast cancer cell growth, The 6th International Symposium on Hormonal Carcinogenesisi in Japan, Sep. 2010.
19.	Tetsuro Yoshimaru, Suzuki Yoshihiro, Inoue Toshio, Nunomura Satoshi and Ra Chisei : Mitochondria calcium flux via the FcepsilonRI beta is critical for calcium mobilization and mast cell activation., Jun. 2006.
20.	Tetsuro Yoshimaru, Suzuki Yoshihiro, Niide Osamu, Inoue Toshio, Matsui Takashi and Ra Chisei : Heavy metals activate mast cells by an oxidant-dependent mechanism: role of redox-sensitive noncapacitative calcium influx., Oct. 2004.
21.	Tetsuro Yoshimaru, Suzuki Yoshihiro, Inoue Toshio, Matsui Takashi, Niide Osamu and Ra Chisei : Heavy metals activate mast cells by an oxidant-dependent mechanism: role of redox-sensitive noncapacitative calcium influx., Jul. 2004.
22.	Tetsuro Yoshimaru, Suzuki Yoshihiro, Yamaki Mitsuo, Ra Chisei and Shimizu Kazufumi : Silver nitrate activates mast cells: Distinctions from FcRI-induced activation., Nov. 2001.
23.	Tetsuro Yoshimaru, Suzuki Yoshihiro, Yamashita Kohei, Matsui Takashi, Yamaki Mitsuo and Shimizu Kazufumi : Role of reactive oxygen species in the high affinity IgE receptor-mediated intracellular signaling to degranulation and mediator., Jul. 2001.
24.	Tetsuro Yoshimaru, Matsui Toshiro, Matsumoto Kiyoshi and Osajima Yutaka : Preparation of Microencapsulated Enzyme for Lowering Allergic Activity of Food., Nov. 1996.

国内講演発表:

1.	篠﨑千穂, 光村豊, 吉丸哲郎, 傳田将也, 片桐豊雅, 大髙章 : 脂肪酸修飾型乳がん増殖抑制ペプチドの開発, 第40回メディシナルケミストリーシンポジウム, 2023年11月.
2.	内山圭司, 吉丸哲郎, 松下洋輔, 尾野雅哉, 三好康雄, 笹三徳, 片桐豊雅 : 乳がん細胞における O型糖鎖修飾を介した IRE1の恒常的活性化機構, 第95回日本生化学会大会, 2022年11月.
3.	Yosuke Matsushita, Kazumasa Okumura, Masato Komatsu, Tetsuro Yoshimaru, Ono Masaya, Akira Tangoku, Miyoshi Yasuo, Sasa Mitsunori and Toyomasa Katagiri : RHBDL2 has essential roles for glutaminolysis and chemoresistance in triple negative breast cancer, The 17th International Symposium of the Institute Network for Biomedical Sciences International Symposium on Tumor Biology in Kanazawa 2022, Oct. 2022.
4.	Tetsuro Yoshimaru, Yosuke Matsushita, Hidetaka Kosako, Sasa Mitsunorii, Miyoshi Yasuo and Toyomasa Katagiri : The plasma membrane BIG3-PHB2 complex contributes to the acquisition of trastuzumab-resistance in HER2-positive breast cancer, The 17th International Symposium of the Institute Network for Biomedical Sciences International Symposium on Tumor Biology in Kanazawa 2022, Oct. 2022.
5.	萩原浩生, 内山圭司, 吉丸哲郎, 松下洋輔, 三好康雄, 笹三徳, 片桐豊雅 : 乳がん細胞におけるO 結合型糖鎖修飾GRP78/Bip の役割解明と創薬研究, 第81回日本癌学会学術総会, 2022年10月.
6.	相原仁, 吉丸哲郎, 尾野雅哉, 笹三徳, 三好康雄, 片桐豊雅 : ミトコンドリアBIG3-PHB2 複合体は，トリプルネガティブ乳癌細胞の脆弱性を示す選択的治療標的である, 第81回日本癌学会学術総会, 2022年10月.
7.	Abdullah S. Ili, Tetsuro Yoshimaru, Yosuke Matsushita, Masato Komatsu, Miyoshi Yasuo, Honda Junko, Ohsumi Shozo, Sasa Mitsunori and Toyomasa Katagiri : Whole-exome sequencing for the identification of Japanese familial breast cancer susceptibility genes, The 81st Annual Meeting of the Japanese Cancer Association, Oct. 2022.
8.	松下洋輔, 奥村和正, 小松正人, 吉丸哲郎, 尾野雅哉, 三好康雄, 笹三徳, 片桐豊雅 : トリプルネガティブ乳癌におけるRHBDL2 のグルタミン代謝調節機構, 第81回日本癌学会学術総会, 2022年10月.
9.	吉丸哲郎, 松下洋輔, 笹三徳, 三好康雄, 片桐豊雅 : 細胞膜BIG3-PHB2 複合体がHER2 陽性乳癌のトラスツズマブ耐性獲得に必須である, 第81回日本癌学会学術総会, 2022年10月.
10.	加藤廉平, 前川滋克, 加藤陽一郎, 兼平貢, 高田亮, 松下洋輔, 吉丸哲郎, 布川朋也, 片桐豊雅, 小原航 : 3 次元培養下における新規の癌特異分子PRELID2 の分子機能の解明, 第81回日本癌学会学術総会, 2022年10月.
11.	内山圭司, 吉丸哲郎, 松下洋輔, 尾野雅哉, 笹三徳, 三好康雄, 片桐豊雅 : 乳がん細胞におけるO 結合型糖転移酵素の発現亢進はIRE1 の恒常的活性化を惹起する, 第81回日本癌学会学術総会, 2022年9月.
12.	相原仁, 吉丸哲郎, 片桐豊雅 : ミトコンドリアBIG3-PHB2複合体ネットワークの脆弱性を標的としたトリプルネガティブ乳癌治療法の開発..., 第26回日本がん分子標的治療学会学術集会, 2022年7月.
13.	松下洋輔, 吉丸哲郎, 片桐豊雅 : トリプルネガティブ乳癌におけるRHBDL2のグルタミン代謝調節機構の解明, 第26回日本がん分子標的治療学会学術集会, 2022年7月.
14.	吉丸哲郎, 松下洋輔, 片桐豊雅 : トラスツズマブ耐性HER2陽性乳がんの克服に向けたBIG3-PHB2相互作用を標的とした持続型阻害ペプチドの開発, 第26回日本がん分子標的治療学会学術集会, 2022年7月.
15.	萩原浩生, 内山圭司, 吉丸哲郎, 松下洋輔, 片桐豊雅 : 乳がん細胞におけるO結合型糖鎖修飾GRP78/Bipの役割解明と創薬研究, 第26回日本がん分子標的治療学会学術集会, 2022年6月.
16.	内山圭司, 松下洋輔, 吉丸哲郎, 萩原浩生, 片桐豊雅 : 乳がん細胞におけるO型糖鎖修飾IRE1経路の恒常的活性化を標的とした新規治療戦略の可能性, 第26回日本がん分子標的治療学会学術集会, 2022年6月.
17.	相原仁, 吉丸哲郎, 尾野雅哉, 笹三徳, 三好康雄, 片桐豊雅 : トリプルネガティブ乳癌細胞のミトコンドリア構造・機能制御におけるBIG3-PHB2複合体の病態生理的役割-癌細胞の脆弱性を標的とした治療法開発, 第44回日本分子生物学会年会, 2021年12月.
18.	松崎淳平, 田代伸也, 新田莉彩子, 尾野雅哉, 吉丸哲郎, 片桐豊雅, 田村康 : ]Split-TurboID-GFPを用いたヒトミトコンドリア-小胞体間コンタクトサイト局在化タンパク質の同定, 第44回日本分子生物学会年会, 2021年12月.
19.	高橋賢司, 田代伸也, 尾野雅哉, 吉丸哲郎, 片桐豊雅, 田村康 : 小胞体-リソソーム間コンタクトサイト局在タンパク質の同定, 第44回日本分子生物学会年会, 2021年12月.
20.	藤本慎太郎, 尾野雅哉, 吉丸哲郎, 片桐豊雅, 田村康 : 出芽酵母におけるミトコンドリア-液胞膜間コンタクトサイト局在タンパク質の同定, 第44回日本分子生物学会年会, 2021年12月.
21.	松下洋輔, 高橋定子, 小松正人, 清谷一馬, 吉丸哲郎, 三好康雄, 本田純子, 紺谷桂一, 大住省三, 笹三徳, 片桐豊雅 : 日本人家族性乳癌家系の新規感受性遺伝子の解析, 日本人類遺伝学会第66回大会第28回日本遺伝子診断学会大会合同開催, 2021年10月.
22.	相原仁, 吉丸哲郎, 尾野雅哉, 笹三徳, 三好康雄, 片桐豊雅 : ミトコンドリアBIG3-PHB2複合体の脆弱性を標的にしたトリプルネガティブ乳癌治療法の可能性考察, 第80回日本癌学会学術総会, 2021年10月.
23.	Tetsuro Yoshimaru, Srinivasan Yuvaraj, Hitoshi Aibara and Toyomasa Katagiri : Disruption of BIG3-PHB2 complex suppresses the proliferation of non-small cell lung cancer., 第80回日本癌学会学術総会, Oct. 2021.
24.	吉丸哲郎, 松下洋輔, 笹三徳, 三好康雄, 片桐豊雅 : HER2陽性乳癌のトラスツズマブ耐性獲得に対するBIG3-PHB2複合体の病態生理学的役割, 第80回日本癌学会学術総会, 2021年10月.
25.	松下洋輔, 小松正人, 清谷一馬, 新沼猛, 鈴木拓, 吉丸哲郎, 田嶋敦, 井本逸勢, 本田純子, 古川洋一, 中村祐輔, 三好康雄, 笹三徳, 片桐豊雅 : SALL3のエピゲノム異常はトリプルネガティブ乳癌の薬剤抵抗性の一因となる, 第80回日本癌学会学術総会, 2021年10月.
26.	光村豊, 小林大志朗, 杉木俊彦, 吉丸哲郎, 倉岡瑛祐, 傳田将也, 藤原敏道, 片桐豊雅, 大髙章 : Cys-Trp 架橋型乳がん抑制ペプチド(ERAP)の合成及び活性評価, 創薬懇話会2021 in 京都, 2021年6月.
27.	吉丸哲郎, 松下洋輔, 片桐豊雅 : トラスツズマブ耐性HER2陽性乳がんに対するBIG3-PHB2相互作用の標的治療薬としての可能性, 第25回日本がん分子標的治療学会学術集会, 2021年5月.
28.	松下洋輔, 小松正人, 清谷一馬, 鈴木拓, 吉丸哲郎, 井本逸勢, 片桐豊雅 : 新規がん抑制因子SALL3不活化はトリプルネガティブ乳癌の化学療法抵抗性に関与する, 第25回日本がん分子標的治療学会学術集会, 2021年5月.
29.	相原仁, 吉丸哲郎, 片桐豊雅 : トリプルネガティブ乳癌細胞においてBIG3-PHB2複合体は癌病態ミトコンドリアを安定制御する, 第25回日本がん分子標的治療学会学術集会, 2021年5月.
30.	相原仁, 吉丸哲郎, 尾野雅哉, 三好康雄, 笹三徳, 片桐豊雅 : トリプルネガティブ乳がん細胞におけるBIG3-PHB2複合体によるミトコンドリア構造・機能制御についての解析, 第43回日本分子生物学会年会, 2020年12月.
31.	土岐俊一, 吉丸哲郎, 相原仁, 松下洋輔, 片桐豊雅 : ミトコンドリア局在BIG3-PHB2複合体の抑制は骨肉腫細胞の悪性化を阻害する, 第24回日本がん分子標的治療学会学術集会, 2020年10月.
32.	相原仁, 吉丸哲郎, 片桐豊雅 : トリプルネガティブ乳癌細胞のミトコンドリア構造・機能制御におけるBIG3-PHB2複合体の病態生理的役割と創薬開発, 第24回日本がん分子標的治療学会学術集会, 2020年10月.
33.	松下洋輔, 吉丸哲郎, 片桐豊雅 : トリプルネガティブ乳癌におけるRHBDL2のグルタミン代謝制御の役割解明, 第24回日本がん分子標的治療学会学術集会, 2020年10月.
34.	吉丸哲郎, 松下洋輔, 片桐豊雅 : BIG3-PHB2標的治療薬によるトラスツズマブ耐性HER2陽性乳がんの克服, 第24回日本がん分子標的治療学会学術集会, 2020年10月.
35.	片桐豊雅, 吉丸哲郎, 松下洋輔 : 乳がん治療耐性克服を目指した抑制因子活性化誘導PPI阻害ペプチドの開発, 第24回日本がん分子標的治療学会学術集会, 2020年10月.
36.	相原仁, 吉丸哲郎, 尾野雅哉, 笹三徳, 三好康雄, 片桐豊雅 : トリプルネガティブ乳癌細胞のミトコンドリア構造・機能制御におけるBIG3-PHB2複合体の病態生理的役割と創薬開発, 第79回日本癌学会学術総会, 2020年10月.
37.	松下洋輔, 小松正人, 清谷一馬, 吉丸哲郎, 新沼猛, 鈴木拓, 本田純子, 井本逸勢, 丹黒章, 三好康雄, 笹三徳, 片桐豊雅 : 新規癌抑制遺伝子SALL3はトリプルネガティブ乳癌の薬剤抵抗性に関与する, 第79回日本癌学会学術総会, 2020年10月.
38.	吉丸哲郎, 松下洋輔, 尾野雅哉, 笹三徳, 三好康雄, 片桐豊雅 : BIG3-PHB2複合体の形成が，HER2陽性乳癌のトラスツズマブ耐性獲得を誘導する, 第79回日本癌学会学術総会, 2020年10月.
39.	土岐俊一, 吉丸哲郎, 相原仁, 松下洋輔, 尾野雅哉, 片桐豊雅 : ミトコンドリアBIG3-PHB2複合体阻害は骨肉腫の悪性化を抑制する, 第79回日本癌学会学術総会, 2020年10月.
40.	土岐俊一, 吉丸哲郎, 相原仁, 松下洋輔, 片桐豊雅 : ミトコンドリア局在BIG3-PHB2複合体の機能抑制は骨肉腫細胞の悪性化を阻害する, 第35回日本整形外科学会基礎学術集会, 2020年10月.
41.	土岐俊一, 吉丸哲郎, 相原仁, 松下洋輔, 西良浩一, 片桐豊雅 : 骨肉腫細胞悪性化におけるBIG3の役割解明と分子間相互作用阻害ペプチド薬による抗腫瘍効果, 第93回日本整形外科学会学術総会, 2020年6月.
42.	安養寺啓太央, 粟飯原圭佑, 吉丸哲郎, 西川祐輔, 小松正人, 重永章, 片桐豊雅, 大髙章 : 乳がん細胞におけるBIG3-PHB2相互作用を標的とした高持続性架橋ペプチドの開発, 日本薬学会第140年会, 2020年3月.
43.	松下洋輔, 小松正人, 清谷一馬, 吉丸哲郎, 新沼猛, 鈴木拓, 本田純子, 井本逸勢, 丹黒章, 三好康雄, 笹三徳, 片桐豊雅 : トリプルネガティブ乳癌の薬剤抵抗性に関与する新規癌抑制遺伝子SALL3の分子機構解明, 第1回日本癌学会若手の会, 2020年2月.
44.	松下洋輔, 高橋定子, 小松正人, 清谷一馬, 吉丸哲郎, 三好康雄, 本田純子, 粕谷桂一, 大住省三, 笹三徳, 片桐豊雅 : 全エキソーム解析による日本人家族性乳がん家系の新規感受性遺伝子の探索, 日本人類遺伝学会第64回大会, 2019年11月.
45.	相原仁, 吉丸哲郎, 尾野雅哉, 笹三徳, 三好康雄, 片桐豊雅 : TNBC細胞のミトコンドリア制御における乳癌特異的分子BIG3の役割, 第78回日本癌学会学術総会, 2019年9月.
46.	吉丸哲郎, 松下洋輔, 笹三徳, 三好康雄, 片桐豊雅 : トラスツズマブ耐性乳がんに関連したBIG3-PHB2相互作用標的治療薬の開発, 第78回日本癌学会学術総会, 2019年9月.
47.	加藤廉平, 布川朋也, 松下洋輔, 吉丸哲郎, 尾野雅哉, 大豆本圭, 加藤陽一郎, 小原航, 片桐豊雅 : 腎癌の癌化におけるPRELID2によるミトコンドリアROS制御機構の解明, 第78回日本癌学会学術総会, 2019年9月.
48.	土岐俊一, 吉丸哲郎, 松下洋輔, 相原仁, 片桐豊雅 : 骨肉腫細胞悪性化におけるBIG3の役割解明と分子間相互作用阻害ペプチド薬による抗腫瘍効果, 第78回日本癌学会学術総会, 2019年9月.
49.	松下洋輔, 奥村和正, 小松正人, 木村竜一朗, 吉丸哲郎, 尾野雅哉, 本田純子, 丹黒章, 三好康雄, 笹三徳, 片桐豊雅 : RHBDL2によるグルタミノリシスの制御はTNBCの悪性化や抗癌剤抵抗性に関連する, 第78回日本癌学会学術総会, 2019年9月.
50.	安養寺啓太央, 粟飯原圭佑, 吉丸哲郎, 重永章, 片桐豊雅, 大髙章 : がん抑制因子PHB2の部分配列を基盤とした乳がん阻害ペプチドの開発, 創薬懇話会2019 in 秋保, 2019年6月.
51.	松下洋輔, 小松正人, 吉丸哲郎, 井本逸成, 鈴木拓, 片桐豊雅 : トリプルネガティブ乳癌におけるがん抑制因子SALL3の不活化機構の解明, 第23回日本がん分子標的治療学会学術集会, 2019年6月.
52.	吉丸哲郎, 松下洋輔, 片桐豊雅 : BIG3複合体によるがん抑制因子PHB2の不活制化を介したトラスツズマブ耐性乳がんの増殖機構と新規治療法, 第23回日本がん分子標的治療学会学術集会, 2019年6月.
53.	土岐俊一, 吉丸哲郎, 松下洋輔, 片桐豊雅 : 骨肉腫細胞悪性化におけるBIG3の役割解明と分子間相互作用阻害ペプチド薬による抗腫瘍効果の検討, 第23回日本がん分子標的治療学会学術集会, 2019年6月.
54.	安養寺啓太央, 粟飯原圭佑, 吉丸哲郎, 重永章, 片桐豊雅, 大髙章 : がん抑制タンパク質PHB2を基盤とした新規創薬シーズの開発, 日本薬学会第139年会, 2019年3月.
55.	吉丸哲郎, 松下洋輔, 片桐豊雅 : 新規Aキナーゼアンカータンパク質BIG3による抑制因子PHB2の制御はHER2乳癌細胞増殖に必須である, 第41回日本分子生物学会年会, 2018年11月.
56.	高橋定子, 松下洋輔, 小松正人, 清谷一馬, 吉丸哲郎, 本田純子, 大住省三, 笹三徳, 片桐豊雅 : 日本人家族性乳がん家系の全エキソーム解析による新規感受性遺伝子の同定及び機能解析, 第77回日本癌学会学術総会, 2018年9月.
57.	加藤廉平, 布川朋也, 吉丸哲郎, 松下洋輔, 尾野雅哉, 大豆本圭, 加藤陽一郎, 小原航, 片桐豊雅 : 腎癌の癌化におけるミトコンドリアPRELID2の重要な役割, 第77回日本癌学会学術総会, 2018年9月.
58.	松下洋輔, 小松正人, 清谷一馬, 吉丸哲郎, 新沼猛, 鈴木拓, 本田純子, 井本逸勢, 丹黒章, 三好康雄, 笹三徳, 片桐豊雅 : トリプルネガティブ乳癌におけるSALL3の高頻度なエピジェネティックな不活化機構, 第77回日本癌学会学術総会, 2018年9月.
59.	大豆本圭, 吉丸哲郎, 松下洋輔, 布川朋也, 上原久典, 尾野雅哉, 小松正人, 金山博臣, 片桐豊雅 : 膀胱癌進展機構おけるDDX31の重要な機能「 TP53ステータスに着目して」, 第77回日本癌学会学術総会, 2018年9月.
60.	吉丸哲郎, 松下洋輔, 笹三徳, 三好康雄, 片桐豊雅 : BIG3-PKA-PP1Cα複合体による癌抑制因子PHB2不活性化を介したトラスツズマブ耐性乳癌増殖機構と新規治療法開発, 第77回日本癌学会学術総会, 2018年9月.
61.	奥村和正, 松下洋輔, 小松正人, 木村竜一朗, 吉丸哲郎, 尾野雅哉, 三好康雄, 本田純子, 笹三徳, 丹黒章, 片桐豊雅 : トリプリネガティブ乳がんにおけるRHBDL2の役割解明と抗体創薬の可能性, 第77回日本癌学会学術総会, 2018年9月.
62.	安養寺啓太央, 粟飯原圭祐, 吉丸哲郎, 重永章, 片桐豊雅, 大髙章 : がん抑制タンパク質PHB2からの創薬シード発掘, 第50回若手ペプチド夏の勉強会, 2018年8月.
63.	松下洋輔, 小松正人, 吉丸哲郎, 片桐豊雅 : トリプルネガティブ乳がんの悪性化におけるRHBDL2の役割解明と創薬開発, 第22回日本がん分子標的治療学会学術集会, 2018年5月.
64.	松下洋輔, 小松正人, 清谷一馬, 吉丸哲郎, 宮川義仁, 本田純子, 井本逸勢, 丹黒章, 鈴木拓, 三好康雄, 笹三徳, 片桐豊雅 : 包括的なゲノム解析によるトリプルネガティブ乳癌の分子特性の解明, 日本人類遺伝学会第62回大会, 2017年11月.
65.	吉丸哲郎, 尾野雅哉, 松下洋輔, 小松正人, 笹三徳, 三好康雄, 片桐豊雅 : BIG3-PKA-PP1Cα複合体による癌抑制因子PHB2不活性化を介したエストロゲン依存性乳癌増殖機構と新規治療法開発, 第76回日本癌学会学術総会, 2017年9月.
66.	高橋定子, 松下洋輔, 小松正人, 吉丸哲郎, 本田純子, 大住省三, 三木義男, 井本逸勢, 三好康雄, 笹三徳, 片桐豊雅 : 日本人家族性乳がん家系の全エキソーム解析による新規家族性乳がん感受性遺伝子の同定, 第76回日本癌学会学術総会, 2017年9月.
67.	松下洋輔, 小松正人, 清谷一馬, 吉丸哲郎, 宮川義仁, 本田純子, 井本逸勢, 丹黒章, 三好康雄, 笹三徳, 片桐豊雅 : TNBCにおける包括的なゲノム解析によるZNFタンパク質のジェネティックかつエピジェネティックな変化の同定, 第76回日本癌学会学術総会, 2017年9月.
68.	大豆本圭, 吉丸哲郎, 布川朋也, 上原久典, 尾野雅哉, 小松正人, 金山博臣, 片桐豊雅 : 筋層浸潤性膀胱癌の多段階進展機構におけるDDX31, Mutant p53, EGFR Axisの役割解明, 第76回日本癌学会学術総会, 2017年9月.
69.	奥村和正, 松下洋輔, 小松正人, 木村竜一朗, 吉丸哲郎, 尾野雅哉, 三好康雄, 本田純子, 笹三徳, 丹黒章, 片桐豊雅 : 《Japanese Oral Sessions》トリプルネガティブ乳がんの悪性化におけるRHBDL2の役割解明, 第76回日本癌学会学術総会, 2017年9月.
70.	木村竜一朗, 松尾泰佑, 尾野雅哉, 吉丸哲郎, 小松正人, 本田純子, 朴在賢, 中村祐輔, 笹三徳, 三好康雄, 片桐豊雅 : ムチン型糖転移酵素GALNT6はLGALS3BPの糖鎖修飾を通じて乳癌発症を制御する．, 第76回日本癌学会学術総会, 2017年9月.
71.	加藤廉平, 布川朋也, 吉丸哲郎, 松下洋輔, 尾野雅哉, 小原航, 片桐豊雅 : 腎癌の癌化におけるPRELID2の重要な役割, 第76回日本癌学会学術総会, 2017年9月.
72.	吉丸哲郎, 松下洋輔, 片桐豊雅 : 分子内架橋型BIG3-PHB2相互作用阻害ペプチドERAPによるホルモン依存性乳がん新規治療法の開発, 第21回日本がん分子標的治療学会学術集会, 2017年6月.
73.	松下洋輔, 小松正人, 吉丸哲郎, 鈴木拓, 井本逸勢, 片桐豊雅 : 全エクソームシーケンス解析によるトリプルネガティブ乳癌の分子特性の解明, 第21回日本がん分子標的治療学会学術集会, 2017年6月.
74.	粟飯原圭佑, 吉丸哲郎, 小松正人, 重永章, 片桐豊雅, 大髙章 : Development of stapled peptides targeting BIG3-PHB2 interaction in breast cancer cells, 第53回ペプチド討論会, 2016年10月.
75.	木村竜一朗, 尾野雅哉, 松尾泰佑, 吉丸哲郎, 三好康雄, 笹三徳, 片桐豊雅 : 糖転移酵素GALNT6はガレクチン結合タンパク質1を糖鎖修飾し，乳癌発症を制御する, 第75回日本癌学会学術総会, 2016年10月.
76.	吉丸哲郎, 松下洋輔, 小松正人, 岡崎泰昌, 豊國伸哉, 笹三徳, 三好康雄, 片桐豊雅 : 内分泌療法耐性乳がんに対するBIG3-PHB2相互作用阻害ペプチドの開発, 第75回日本癌学会学術総会, 2016年10月.
77.	瀧亮祐, 吉丸哲郎, 大豆本圭, 松下洋輔, 木村竜一朗, 尾野雅哉, 片桐豊雅 : BIG3-PHB2相互作用を標的とした前立腺がん治療法の開発の可能性, 第75回日本癌学会学術総会, 2016年10月.
78.	奥村和正, 小松正人, 木村竜一朗, 尾野雅哉, 吉丸哲郎, 松下洋輔, 三好康雄, 本田純子, 笹三徳, 丹黒章, 片桐豊雅 : トリプルネガティブ乳癌で高発現が認められるTNRHP1の発現亢進は癌の悪性度と相関する, 第75回日本癌学会学術総会, 2016年10月.
79.	松下洋輔, 小松正人, 清谷一馬, 吉丸哲郎, 宮川義仁, 本田純子, 井本逸勢, 丹黒章, 三好康雄, 笹三徳, 片桐豊雅 : 全エキソーム解析によるトリプルネガティブ乳癌の分子特性の解明, 第75回日本癌学会学術総会, 2016年10月.
80.	吉丸哲郎, 小松正人, 片桐豊雅 : ホルモン療法耐性乳がん治療を目的とした分子内架橋型BIG3-PHB2相互作用阻害ペプチドの開発, 第20回日本がん分子標的治療学会学術集会, 2016年6月.
81.	金南希, 吉丸哲郎, 片桐豊雅, 田中栄二 : 乳がん細胞におけるがん抑制分子PHB2のエストロゲン依存性核内移行機序の解明, 第74回日本矯正歯科学会大会プログラム・抄録集, 194, 2015年11月.
82.	片桐豊雅, 小松正人, 清谷一馬, 吉丸哲郎, 井本逸勢, 笹三徳, 三好康雄 : トリプルネガティブ乳癌における癌抑制遺伝子ZNFXの同定と不活化機構の解明, 日本人類遺伝学会第60会大会, 2015年10月.
83.	大豆本圭, 小松正人, 木村竜一朗, 吉丸哲郎, 上原久典, 尾野雅哉, 布川朋也, 金山博臣, 片桐豊雅 : P53変異型膀胱癌におけるDEAD box polypeptide31(DDX31)の機能解明, 第74回日本癌学会学術総会, 2015年10月.
84.	宮川義仁, 小松正人, 清谷一馬, 吉丸哲郎, 本田純子, 笹三徳, 三好康雄, 片桐豊雅 : トリプルネガティブ乳癌における癌抑制遺伝子BCLR1の発現低下について, 第74回日本癌学会学術総会, 2015年10月.
85.	吉丸哲郎, 小松正人, 田代悦, 長田裕之, 井本正哉, 豊國伸哉, 三好康雄, 笹三徳, 片桐豊雅 : エストロゲン受容体制御分子BIG3を標的とした新規ER陽性乳がんの治療法, 第74回日本癌学会学術総会, 2015年10月.
86.	吉丸哲郎, 小松正人, 田代悦, 長田裕之, 井本正哉, 片桐豊雅 : エストロゲン受容体制御分子BIG3を標的とした新規ER陽性乳がん治療法の開発, 日本がん分子標的治療学会第19回学術集会, 2015年6月.
87.	小松正人, 吉丸哲郎, 井本逸勢, 片桐豊雅 : トリプルネガティブ乳癌における新規腫瘍抑制遺伝子Zing finger protein-X(ZNFX)の不活化機構の解明, 日本がん分子標的治療学会第19回学術集会, 2015年6月.
88.	大豆本圭, 小松正人, 吉丸哲郎, 金山博臣, 片桐豊雅 : 膀胱癌悪性化規定因子である新規核小体蛋白質DDX31の機能解析, 日本がん分子標的治療学会第19回学術集会, 2015年6月.
89.	片桐豊雅, 吉丸哲郎, 小松正人, 田代悦, 井本正哉, 長田裕之 : エストロゲン受容体制御分子BIG3を標的とした新規ホルモン依存性乳がん治療法の開発, 日本農芸化学会 2015年度(平成27年度)大会, 2015年3月.
90.	片桐豊雅, 吉丸哲郎, 小松正人 : 新規エストロゲンシグナル制御分子BIG3による新たながん抑制因子prohibitin2の機能喪失機構の解明, 第87回日本生化学学会大会, 2014年10月.
91.	宮川義仁, 小松正人, 清谷一馬, 吉丸哲郎, 笹三徳, 三好康雄, 片桐豊雅 : トリブルネガティブ乳癌における癌抑制遺伝子BCLR1の発現低下について, 第73回日本癌学会学術総会, 2014年9月.
92.	金南希, 吉丸哲郎, 小松正人, 松尾泰佑, 笹三徳, 片桐豊雅 : 乳癌細胞における癌抑制分子PHB2のエストロゲン依存性核内移行機構の解明, 第73回日本癌学会学術総会, 2014年9月.
93.	小松正人, 吉丸哲郎, 尾野雅哉, 松尾泰佑, 清谷一馬, 三好康雄, 笹三徳, 片桐豊雅 : 悪性度の高いトリプルネガティブ乳癌における核内19S-proteasome関連遺伝子(nPAG1)の役割, 第73回日本癌学会学術総会, 2014年9月.
94.	吉丸哲郎, 小松正人, 三好康雄, 笹三徳, 片桐豊雅 : エストロゲン受容体制御分子BIG3を標的とした新規ER陽性乳がん治療法の開発, 第73回日本癌学会学術総会, 2014年9月.
95.	大豆本圭, 小松正人, 吉丸哲郎, 上原久典, 布川朋也, 金山博臣, 片桐豊雅 : 核小体がんタンパク質BCRG1は膀胱癌の進行に関連している, 第73回日本癌学会学術総会, 2014年9月.
96.	小松正人, 吉丸哲郎, 松尾泰佑, 片桐豊雅 : トリプルネガティブ乳癌におけるプロテアソーム構成因子のプロテアソーム活性非依存的な役割, 第18回日本がん分子標的治療学会学術集会, 2014年6月.
97.	吉丸哲郎, 小松正人, 松尾泰佑, 片桐豊雅 : エストロゲン受容体制御分子BIG3を標的とした新規ER陽性乳がんの治療法の創製, 第18回日本がん分子標的治療学会学術集会, 2014年6月.
98.	吉丸哲郎, 小松正人, 松尾泰佑, 三好康雄, 笹三徳, 中村祐輔, 片桐豊雅 : エストロゲン受容体活性化制御分子ERAP1と腫瘍抑制因子REAの相互作用を標的とした内分泌療法耐性乳癌の治療法の開発, 第72回日本癌学会学術総会, 2013年10月.
99.	松尾泰佑, 尾野雅哉, 吉丸哲郎, 小松正人, 三好康雄, 笹三徳, 片桐豊雅 : がん特異的糖転移酵素BCGT1による小胞体ストレス制御を介した新規乳癌細胞増殖機構の解明, 第72回日本癌学会学術総会, 2013年10月.
100.	柳井亜矢子, 小松正人, 吉丸哲郎, 清谷一馬, 伊藤敬, 廣田誠一, 笹三徳, 片桐豊雅, 三好康雄 : 免疫組織染色によるER陽性Her2陰性乳癌の分子生物学的特徴, 第72回日本癌学会学術総会, 2013年10月.
101.	Masato Komatsu, Tetsuro Yoshimaru, Taisuke Matsuo, Kazuma Kiyotani, Miyoshi Yasuo, Sasa Mitsunori and Toyomasa Katagiri : Nuclear-19S proteasome associated gene 1 contributes to the aggressiveness of triple negative breast cancer cells, 72nd Annual Meeting of the Japanese Cancer Association, Oct. 2013.
102.	松尾泰佑, 吉丸哲郎, 片桐豊雅 : 新規糖転移酵素BCGT1による小胞体ストレス応答制御を介した乳癌細胞増殖機構の解明, 第17回日本がん分子標的治療学会学術集会, 2013年6月.
103.	小松正人, 吉丸哲郎, 松尾泰佑, 中村祐輔, 片桐豊雅 : ゲノムワイドな網羅的遺伝子発現情報解析を用いたトリプルネガティブ乳癌(TNBC)の分子特性および新たな治療標的の探索, 第17回日本がん分子標的治療学会学術集会, 2013年6月.
104.	吉丸哲郎, 小松正人, 松尾泰佑, 片桐豊雅 : ERα活性化制御分子ERAP1を標的とした内分泌療法耐性乳癌の治療戦略, 第17回日本がん分子標的治療学会学術集会, 2013年6月.
105.	小松正人, 吉丸哲郎, 松尾泰佑, 清谷一馬, 柳井亜矢子, 片桐豊雅 : トリプルネガティブ乳癌におけるプロテアソーム関連因子PAG1による新規増殖機構の解明, 第246回徳島医学会学術集会(平成24年度冬期), 2013年2月. (キーワード) 国内学会
106.	清谷一馬, 藤本明洋, 小松正人, 吉丸哲郎, 松尾泰佑, 角田達彦, 三好康雄, 笹光徳, 片桐豊雅 : トリプルネガティブ乳がんのエクソーム解析, 第71回日本癌学会学術総会, 2012年9月.
107.	小松正人, 吉丸哲郎, 松尾泰佑, 清谷一馬, 三好康雄, 島田光生, 中村祐輔, 笹光徳, 片桐豊雅 : トリプルネガティブ乳癌におけるプロテアソーム関連遺伝子PAG1 を介した発癌・増殖機構の関与, 第71回日本癌学会学術総会, 2012年9月.
108.	吉丸哲郎, 小松正人, 松尾泰佑, 三好康雄, 笹光徳, 中村祐輔, 片桐豊雅 : ER陽性乳癌において，ERAP1は腫瘍抑制因子REAとの結合を介してエストロゲンシグナルの恒常的活性化を導く．, 第71回日本癌学会学術総会, 2012年9月.
109.	片桐豊雅, 吉丸哲郎, 松尾泰佑, 中村祐輔, 三好康雄, 笹光徳 : 乳癌における新規分子標的治療薬開発戦略, 第71回日本癌学会学術総会, 2012年9月.
110.	松尾泰佑, 尾野雅哉, 吉丸哲郎, 三好康雄, 笹光徳, 中村祐輔, 片桐豊雅 : 新規糖転移酵素BCGT1による小胞体ストレス応答制御を介した乳癌細胞増殖機構の解明, 第71回日本癌学会学術総会, 2012年9月.
111.	Le T. Dat, Taisuke Matsuo, Tetsuro Yoshimaru, Souji Kakiuchi, Hisatsugu Goto, Kuramoto Takuya, Mitsuhashi Atsushi, Saburo Sone, Yasuhiko Nishioka and Toyomasa Katagiri : LBMTF a novel transcriptional factor involved in lung cancer bone metastases, The 71th Annual Meeting of the Japanese Cancer Association, Sep. 2012.
112.	小松正人, 吉丸哲郎, 松尾泰佑, 清谷一馬, 三好康雄, 島田光生, 中村祐輔, 笹三徳, 片桐豊雅 : Involvement of proteasome-associated gene 1 (PAG1) in proliferation of triple negative breast cancer. (トリプルネガティブ乳癌におけるプロテアソーム関連遺伝子PAG1を介した発癌・増殖機構の関与), 第71回日本癌学会学術総会, 2012年9月. (キーワード) 国内学会
113.	Le T. Dat, Taisuke Matsuo, Tetsuro Yoshimaru, Takuya Kuramoto, Masaki Hanibuchi, Hisatsugu Goto, Souji Kakiuchi, Yasuhiko Nishioka, Saburo Sone and Toyomasa Katagiri : Genome-wide gene expression profiling analysis of bone metastases of human non-smal cell lung cancer (NSCLC) in mice, 70th Annual Meeting of the Japanese Cancer Association, Oct. 2011.
114.	Komatsu Masato, Tetsuro Yoshimaru, Taisuke Matsuo, Miyoshi Yasuo, Mitsuo Shimada, Nakamura Yusuke, Sasa Mitsunori, Miyano Satoru and Toyomasa Katagiri : Novel therapeutic strategy for Triple Negative Breast Cancer, Proceedings of the Japanese Cancer Association, 237, Oct. 2011.
115.	小松正人, 吉丸哲郎, 松尾泰佑, 中村祐輔, 片桐豊雅 : Triple negative breast cancer(TNBC)における新規増殖シグナル経路および治療標的分子同定の試み, 第15回日本がん分子標的治療学会学術集会, 2011年6月.
116.	片桐豊雅, 吉丸哲郎, 松尾泰佑, 三好康雄, 笹三徳, 中村祐輔 : 新規エストロゲン受容体活性化制御分子による乳癌細胞増殖機構の解明, 第11回ホルモンと癌研究会, 2010年7月.
117.	吉丸哲郎, 松尾泰佑, 中村祐輔, 片桐豊雅 : 新規エストロゲン受容体制御分子によるホルモン依存性乳がん増殖機構の解明, 第14回日本がん分子標的治療学会学術集会, 2010年7月.
118.	小松正人, 吉丸哲郎, 松尾泰佑, 片桐豊雅 : --, 第18回日本がん分子標的治療学会学術集会, 2004年6月.

その他・研究会:

1.	松下洋輔, 小松正人, 清谷一馬, 吉丸哲郎, 宮川義仁, 本田純子, 井本逸勢, 丹黒章, 三好康雄, 笹三徳, 片桐豊雅 : 次世代シーケンス解析によるトリプルネガティブ乳癌の分子特性の解明, 第75回徳島乳腺研究会, 2016年4月.
2.	木村竜一朗, 吉丸哲郎, 小松正人, 三好康雄, 笹三徳, 片桐豊雅 : トリプルネガティブ乳癌の発症・進展におけるBIG3の役割, 平成26年度がん若手研究者ワークショップ, 2014年9月.
3.	吉丸哲郎, 石田真由美, 片桐豊雅 : 難治性乳癌克服にむけた新規エストロゲン受容体活性化制御分子ERAP1の機能解明, 平成25年度がん若手研究者ワークショップ, 2013年9月.
4.	小松正人, 吉丸哲郎, 松尾泰佑, 清谷一馬, 斉藤あゆむ, 山口類, 宮野悟, 三好康雄, 笹三徳, 中村祐輔, 片桐豊雅 : トリプルネガティブ乳癌(TNBC)の増殖における26Sプロテアソーム関連遺伝子の役割, 平成24年度がん若手研究者ワークショップ, 2012年9月.
5.	松尾泰佑, 尾野雅哉, 吉丸哲郎, 三好康雄, 笹三徳, 中村祐輔, 片桐豊雅 : Identification of characterization of a novel glycosyltrasnferase BCGT1 involved in breast cancer cells, 平成23年度がん若手研究者ワークショップ, 2011年9月. (キーワード) システムがん

科学研究費補助金 (KAKEN Grants Database @ NII.ac.jp)

BIG3-PHB2複合体を標的としたHER2陽性乳がんの薬剤耐性を克服する多角的がん治療戦略 (研究課題/領域番号: 23H02970 )
HER2陽性乳癌の薬剤耐性獲得における乳癌特異的分子BIG3の病態生理学的意義 (研究課題/領域番号: 20K08958 )
乳がんにおける休眠抑制因子群再活性化を利用した創薬研究 (研究課題/領域番号: 17K19601 )
ミトコンドリアを介した活性酸素制御による乳癌のホルモン療法耐性機構の解明 (研究課題/領域番号: 17K10551 )
乳がん細胞における新規エストロゲン受容体活性制御分子BIG3の病態機能の解明 (研究課題/領域番号: 16H05153 )
新規ER制御分子BIG3を介した内分泌療法耐性機構の解明および新規治療法の開発 (研究課題/領域番号: 26461948 )
新規エストロゲン受容体活性制御分子の生体機能解明と創薬研究 (研究課題/領域番号: 25293079 )
次世代シークエンサーによる新規乳がん関連遺伝子の探索 (研究課題/領域番号: 24501342 )
ミトコンドリア由来活性酸素を標的とした免疫難病治療の新戦略 (研究課題/領域番号: 21790293 )
喘息患者好中球のFcεRIを介した活性酸素種の産生と炎症増幅因子としての役割 (研究課題/領域番号: 19790696 )
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准教授 : 吉丸哲郎

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科学研究費補助金 (KAKEN Grants Database @ NII.ac.jp)

准教授 : 吉丸 哲郎

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科学研究費補助金 (KAKEN Grants Database @ NII.ac.jp)

准教授 : 吉丸哲郎