Phosphorylation of SWI/SNF chromatin remodeling component Brg1 and mechanisms involved in malignant transformation of cancer

• Project/Area Number: 15K19028
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Pathological medical chemistry
• Research Institution: Yokohama City University
• Principal Investigator: KIMURA Ayuko 横浜市立大学, 先端医科学研究センター, 特任助教 (50553616)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2015: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: リン酸化 / 癌 / 悪性化 / プロテオミクス / クロマチン再構成複合体 / 卵巣明細胞癌 / 悪性度 / SWI/SNF複合体 / Brg1 / OCCC / 卵巣癌 / SWI/SNF / 質量分析

Outline of Final Research Achievements

The SWI/SNF complex contains many tumor suppressors (e.g., ARID1A and BRG1) that are frequently mutated in cancers including ovarian clear cell carcinoma (OCCC), a malignant subtype of ovarian cancers. Previously, we reported that the phosphorylation of BRG1 was significantly reduced in OCCC cells. To reveal the role of BRG1 phosphorylation, we analyzed the transcriptome, proteome, and phenotypes of cell lines with or without mutations in the phosphorylation site.
Proteome analysis revealed the upregulation of proteins and phosphoproteins involved in chromatin inactivation in phosphorylation-mimic mutant. In addition, the proliferative and migratory abilities of phosphorylation-mimic cells was decreased as compared to those of wild-type or phosphorylation-deleted cells. Transcriptome analysis also revealed their quantitative differences in genes involved in cell proliferation and migration, indicating the role of BRG1 phosphorylation in regulation of these genes.

Research Products

• [Journal Article] Serum quantitative proteomic analysis reveals soluble EGFR to be a marker of insulin resistance in male mice and humans. (2017)
  • Author(s): Kyohara M, Shirakawa J, Okuyama T, Kimura A, Togashi Y, Tajima K, Hirano H, Terauchi Y.
  • Journal Title: Endocrinology Volume: 158(12) Issue: 12 Pages: 4152-4164
  • DOI: 10.1210/en.2017-00339
  • Peer Reviewed / Open Access
• [Journal Article] 癌悪性化機構の解明を目指したリン酸化プロテオーム解析 (2017)
  • Author(s): 木村 鮎子、平野 久
  • Journal Title: Proteome Letters Volume: 2 Pages: 37-45
  • NAID: 130007529343
  • Peer Reviewed / Open Access
• [Journal Article] Lyn Kinase Suppresses the Transcriptional Activity of IRF5 in the TLR-MyD88 Pathway to Restrain the Development of Autoimmunity. (2016)
  • Author(s): Ban T., Sato G.R., Nishiyama A., Akiyama A., Takasuna M., Umehara M., Suzuki S., Ichino M., Matsunaga S., Kimura A., Kimura Y., Yanai H., Miyashita S., Kuromitsu J., Tsukahara K., Yoshimatsu K., Endo I., Yamamoto T., Hirano H., Ryo A., Taniguchi T., Tamura T.
  • Journal Title: Immunity Volume: 45 Issue: 2 Pages: 319-332
  • DOI: 10.1016/j.immuni.2016.07.015
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Comprehensive behavioral study and proteomic analyses of CRMP2-deficient mice. (2016)
  • Author(s): Nakamura H, Yamashita N, Kimura A, Kimura Y, Hirano H, Makihara H, Kawamoto Y, Jitsuki-Takahashi A, Yonezaki K, Takase K, Miyazaki T, Nakamura F, Tanaka F, Goshima Y.
  • Journal Title: Genes to Cells Volume: 21 Issue: 10 Pages: 1059-1079
  • DOI: 10.1111/gtc.12403
  • Peer Reviewed / Open Access
• [Journal Article] Biological significance of co- and post-translational modifications of the yeast 26S proteasome. (2016)
  • Author(s): Hirano H, Kimura Y, Kimura A
  • Journal Title: J. proteomics Volume: 134 Pages: 37-46
  • DOI: 10.1016/j.jprot.2015.11.016
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] N-myristoylation of the Rpt2 subunit of the yeast 26S proteasome is implicated in the subcellular compartment-specific protein quality control system. (2016)
  • Author(s): Kimura A, Kurata Y, Nakabayashi J, Kagawa H, Hirano H.
  • Journal Title: J. proteomics Volume: 130 Pages: 33-41
  • DOI: 10.1016/j.jprot.2015.08.021
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] クロマチン再構成複合体因子BRG1のリン酸化修飾によるクロマチン関連タンパク質の変化と遺伝子発現制御 (2017)
  • Author(s): 木村 鮎子、中林 潤、田村 智彦、香川 裕之、木村 弥生、平野 久
  • Organizer: 2017年度 生命科学系学会合同年次大会 (第40回 日本分子生物学会年会)
• [Presentation] Proteome and transcriptome analyses of phosphorylation site-specific mutants of BRG1, a chromatin remodeling component (2017)
  • Author(s): Ayuko Kimura, Jun Nakabayashi, Tomohiko Tamura, Hiroyuki Kagawa, Yayoi Kimura, and Hisashi Hirano
  • Organizer: 16th Human Proteome Organization World Congress (HUPO2017)
  • Int'l Joint Research
• [Presentation] Effects of phosphorylation site-specific mutations in a component of chromatin remodeling complex (2017)
  • Author(s): Ayuko Kimura
  • Organizer: 日本プロテオーム学会2017年大会
  • Invited
• [Presentation] (受賞講演)癌悪性化機構の解明を目指したリン酸化プロテオーム解析 (2016)
  • Author(s): 木村 鮎子
  • Organizer: 日本プロテオーム学会2016年大会（JHUPO第14回大会）
  • Place of Presentation: 北里大学白金キャンパス (東京都港区)
  • Year and Date: 2016-07-29
• [Presentation] 癌悪性化機構の解明を目指したリン酸化プロテオーム解析 (2016)
  • Author(s): 木村 鮎子
  • Organizer: 日本プロテオーム学会2016年大会 （JHUPO第14回大会）
  • Place of Presentation: 北里大学
  • Year and Date: 2016-07-28
  • Invited
• [Presentation] 卵巣明細胞腺癌の悪性化機構の解明を目指したリン酸化プロテオーム解析 (2016)
  • Author(s): 木村 鮎子
  • Organizer: 第13回 北里疾患プロテオーム研究会/第66回 日本電気泳動学会シンポジウム
  • Place of Presentation: 北里大学
  • Year and Date: 2016-03-25
  • Invited
• [Presentation] 酵母26SプロテアソームサブユニットのN-ミリストイル化修飾とタンパク質品質管理 (2015)
  • Author(s): 木村 鮎子、倉田 洋一、香川 裕之、平野 久
  • Organizer: 第38回 日本分子生物学会年会
  • Place of Presentation: 神戸ポートアイランド
  • Year and Date: 2015-12-03
• [Book] In silico創薬におけるスクリーニングの高速化・効率化技術, 6章 システムバイオロジーによる疾患研究およびバイオマーカー探索の具体的事例, 第2節 プロテオミクスによる疾病研究とバイオマーカー探索 (2018)
  • Author(s): 木村 鮎子 (分担執筆)
  • Total Pages: 540
  • Publisher: 技術情報協会
  • ISBN: 9784861046889