Elucidation for molecular mechanisms of neoplastic cell transformation

• Project/Area Number: 23300347
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Tumor biology
• Research Institution: Jikei University School of Medicine (2012-2013); Tokyo Medical and Dental University (2011)
• Principal Investigator: YOSHIDA Kiyotsugu 東京慈恵会医科大学, 医学部, 教授 (70345312)
• Project Period (FY): 2011-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥21,450,000 (Direct Cost: ¥16,500,000、Indirect Cost: ¥4,950,000); Fiscal Year 2013: ¥8,580,000 (Direct Cost: ¥6,600,000、Indirect Cost: ¥1,980,000); Fiscal Year 2012: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000); Fiscal Year 2011: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
• Keywords: DNA傷害 / アポトーシス / ユビキチン化 / プロテオミクス / 癌 / リン酸化酵素 / 細胞周期

Research Abstract

Dysregulation of the G1/S transition in the cell cycle contributes to tumor development. Degradation of c-Jun/c-Myc is a critical process for the G1/S transition. We found DYRK2 functioning as a priming kinase, whose phosphorylation of c-Jun/c-Myc precedes and is required for subsequent GSK3beta phosphorylation. DYRK2 silencing shortened the G1 phase to accelerate cell proliferation due to their escape from ubiquitination-mediated degradation.
EMT plays a fundamental role in the early stages of breast cancer invasion. Snail is an important regulator of EMT. We identified that DYRK2 regulates Snail stability. Knockdown of DYRK2 promoted EMT and cancer invasion in vitro and in vivo.
p53 phosphorylation at Ser46 exerts apoptotic cell death. We found that amphiregulin (AREG) is identified for a direct target of Ser46 phosphorylation. AREG interacted with DDX5. AREG regulated precursor microRNA processing with DDX5 to reduce the expression of anti-apoptotic protein Bcl-2.

Research Products

• [Journal Article] Induction of amphiregulin by p53 promotes apoptosis via control of microRNA biogenesis in response to DNA damage (2014)
  • Author(s): Taira N, Yamaguchi T, Kimura J, Lu Z-G, Fukuda S, Higashiyama S, Ono M, Yoshida K
  • Journal Title: Proc. Natl. Acad. Sci. USA Volume: 111 Issue: 2 Pages: 717-722
  • DOI: 10.1073/pnas.1313675111
  • Peer Reviewed / Open Access
• [Journal Article] DYRK2 controls epithelial-mesenchymal transition in breast cancer by degrading Snail (2013)
  • Author(s): Mimoto R, Taira N, Takahashi H, Yamaguchi T, Okabe M, Uchida K, Miki Y, Yoshida K
  • Journal Title: Cancer Lett Volume: 339 Issue: 2 Pages: 214-225
  • DOI: 10.1016/j.canlet.2013.06.005
  • Peer Reviewed
• [Journal Article] DYRK2 priming phosphorylation of c-Jun and c-Myc modulates cell cycle progression in human cancer cells (2012)
  • Author(s): Taira N., et al
  • Journal Title: The Journal of Clinical Investigation Volume: 122 Issue: 3 Pages: 859-872
  • DOI: 10.1172/jci60818
  • Peer Reviewed
• [Journal Article] Programmed cell death 6, a novel p53-responsive gene, targets to the nucleus in the apoptotic response to DNA damage. (2012)
  • Author(s): Kazuho Suzuki
  • Journal Title: Cancer Sci. Volume: 103 Issue: 10 Pages: 1788-1794
  • DOI: 10.1111/j.1349-7006.2012.02362.x
  • Peer Reviewed
• [Journal Article] DYRK2 priming phosphorylation of c-Jun and c-Myc modulates cell cycle progression in human cancer cells (2012)
  • Author(s): Taira, et al
  • Journal Title: J Clin.Invest. Volume: 122 Pages: 859-872
  • Peer Reviewed
• [Journal Article] PKCdelta regulates Mdm2 independently of p53 in the apoptotic response to DNA damage (2011)
  • Author(s): Hew, et al
  • Journal Title: Mol.Carcinog. Volume: 50 Pages: 719-731
  • Peer Reviewed
• [Journal Article] Identification of Evi-1 as a novel effector of PKCdelta in the apoptotic response to DNA damage (2011)
  • Author(s): Hew, et al
  • Journal Title: Biochim.Biopbys.Acta Volume: 1803 Pages: 285-294
  • Peer Reviewed
• [Presentation] 細胞死及びmicroRNA代謝制御に関わる新規p53関連遺伝子の同定 (2013)
  • Author(s): 平直江 他
  • Organizer: 第７２回日本癌学会学術総会
  • Place of Presentation: 横浜
• [Presentation] Mps1/TKは分裂期染色体凝集を制御する (2013)
  • Author(s): 加賀美裕也 他
  • Organizer: 第７２回日本癌学会学術総会
  • Place of Presentation: 横浜
• [Presentation] P53 targets isoform of paralemmin protein in a serine 46 specific manner to promote apoptosis (2013)
  • Author(s): Nurmaa DASHZEVEG, et al.
  • Organizer: 第７２回日本癌学会学術総会
  • Place of Presentation: 横浜
• [Presentation] Epoxomicin耐性細胞はDUSP6/MKP3発現消失に伴いZEB1発現を誘導しE-cadherin発現消失を促す (2013)
  • Author(s): 朝倉正 他
  • Organizer: 第７２回日本癌学会学術総会
  • Place of Presentation: 横浜
• [Presentation] DYRK2 phosphorylation of c-Jun/c-Myc controls tumor progression by monitoring G1/S transition. (2013)
  • Author(s): Kiyotsugu Yoshida
  • Organizer: 1st International Symposium on Protein Modifications in Pathogenic Dysregulation of Signaling
  • Place of Presentation: Tokyo, Japan
  • Invited
• [Presentation] 細胞死誘導と細胞周期制御による発癌抑制の分子機構 (2012)
  • Author(s): 吉田清嗣
  • Organizer: 第3次対がん10か年総合戦略・文科省がん支援活動 合同公開シンポジウム
  • Place of Presentation: 東京
  • Year and Date: 2012-01-31
• [Presentation] 細胞死誘導と細胞周期制御による発癌抑制の分子機構 (2012)
  • Author(s): 吉田清嗣
  • Organizer: 第3次対がん10か年総合戦略・文科省がん支援活動合同公開シンポジウム
  • Place of Presentation: 東京
  • Year and Date: 2012-01-31
• [Presentation] Role for DYRK2 in cell cycle control and tumor progression. (2012)
  • Author(s): Kiyotsugu Yoshida
  • Organizer: MMC2012
  • Place of Presentation: Bangkok, Thailand
• [Book] Functional role for the c-Abl tyrosine kinase signalling in the DNA damage response. In : Kimura S and Shimizu S (eds), DNA repair : New Research (2012)
  • Author(s): Yoshida K
  • Publisher: Nova Science Publishers, Inc
• [Book] Role for PKCδ on apoptosis in the DNA damage response. In : Clark C. Chen (ed), Selected T opics in DNA Repair (2011)
  • Author(s): Yoshida K
  • Publisher: InTech
• [Remarks]
  • URL: http://jikei-biochem.wix.com/yoshidalab
• [Remarks] 東京慈恵会医科大学生化学講座ホームページ
  • URL: http://jikei-biochem.wix.com/yoshidalab