Mechanism of ovarian carcinogenesis due to 26S proteasome activation by protooncogene gankyrin mononeddylation

• Project/Area Number: 24592514
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Obstetrics and gynecology
• Research Institution: Kyoto University
• Principal Investigator: HIGASHITSUJI Hisako 京都大学, 医学(系)研究科(研究院), 助教 (20402852)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2014: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2013: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2012: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: gankyrin / mononeddylation / S6 ATPase / 26S proteasome / polyubiquitylation / synthetic biology / mdm2 / p53 / NEDD8 / E3 ubiquitin ligase / pRB / 卵巣がん / ガンキリン / プロテアソーム / 卵巣癌 / 癌遺伝子

Outline of Final Research Achievements

In ovarian cancers, gankyrin and Nedd8 are overexpressed. In vitro gankyrin neddylation assay (bacteria-expressed and purified E1, E2, Mdm2, Nedd8, gankyrin, ATP) produces gankyrin mononeddylation, that is verified by western blot of anti-gankyrin antibody and anti-Nedd8 antibody. Due to synthetic biological method, polycistronic affinity-tagged gankyrin, Nedd8, E1, E2, and Mdm2 are expressed into Rosetta bacterial cells. Gankyrin mononeddylation occurs. This expressed and purified mononeddylated gankyrin enhances p53 and pRB polyubiquitylation and 26S proteasome-mediated protein degradation. This effect is enhanced by full-length S6 ATPase co-expression. However it is suppressed by C-terminal truncated S6 ATPase mutant.

Research Products

• [Journal Article] Biallelic DICER1 mutations in sporadic pleuropulmonary blastoma (2018)
  • Author(s): Sakai, E., Nakayama, M., Oshima, H., Kouyama, Y., Niida, A., Fujii, S., Ochiai, A., Nakayama, K. I., Mimori, K., Suzuki, Y., Hong, C. P., Ock, C. Y., Kim, S. J. and Oshima, M.
  • Journal Title: Cancer Research Volume: in press Pages: 1283-1295
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Mechanistic insights into human pre-mRNA splicing of human ultra-short introns: potential unusual (2018)
  • Author(s): Suzuki S, Hoshino H, Yoshida K, Nakanishi J, Tsuchiya-Hirata S, Kobuke S, Haruyama N, Nishimura F, Shiba H.
  • Journal Title: Biochemical and biophysical research communications. Volume: 495 Pages: 100-106
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Hypothermia protects against fulminant hepatitis in mice by reducing reactive oxygen species production (2013)
  • Author(s): Sakurai T, Kudo M, Watanabe T, Itoh K, Higashitsuji H, Arizumi T, Inoue T, Hagiwara S, Ueshima K, Nishida N, Fukumoto M, Fujita J.
  • Journal Title: Digestive Diseases Volume: 31 Pages: 440-446
  • DOI: 10.1159/000355242
  • Peer Reviewed
• [Journal Article] Identification of a novel enhancer that binds Sp1 and contributes to induction of cold-inducible RNA-binding protein (cirp) expression in mammalian cells. (2012)
  • Author(s): Sumitomo Y, Higashitsuji H, Higashitsuji H, Liu Y, Fujita T, Sakurai T, et al
  • Journal Title: BMC Biotechnol. Volume: 12 Pages: 72-72
  • DOI: 10.1186/1472-6750-12-72
  • Peer Reviewed
• [Journal Article] Cold-inducible RNA-binding protein (Cirp) interacts with Dyrk1b/Mirk and promotes proliferation of immature male germ cells in mice. (2012)
  • Author(s): Masuda T, et al.
  • Journal Title: Proc Natl Acad Sci U S A. Volume: 109 Pages: 90-10885
  • DOI: 10.1073/pnas.1121524109
  • Peer Reviewed
• [Presentation] ほ乳類低温ショックタンパク質CIRPはBRCA1による相同組み替えによるDNA修復を促進する (2014)
  • Author(s): 東辻久子
  • Organizer: 第６９回日本消化器外科学会総会
  • Place of Presentation: 郡山市立文化センター
  • Year and Date: 2014-07-16 – 2014-07-18
• [Presentation] ほ乳類低温ショックタンパク質Cirpは皮膚創傷治癒を促進する (2013)
  • Author(s): 藤田潤、東辻久子、東辻宏明
  • Organizer: 第８回臨床ストレス応答学会
  • Place of Presentation: 松本市、信州大学医学部付属病院、大会議室
• [Presentation] Overexpression of gankyrin in mouse hepatocytes induces hemangioma. (2013)
  • Author(s): 東辻宏明、東辻久子、藤田潤
  • Organizer: 第２１回JDDW２０１３
  • Place of Presentation: 東京都品川区
• [Presentation] ACC1脂質代謝系酵素によるBRCA1のhomologous recombination の調節機序 (2013)
  • Author(s): 東辻宏明、東辻久子
  • Organizer: 日本消化器病学会
  • Place of Presentation: 鹿児島市