Molecular mechanism of oncogenic RAS-induced gene silencing

• Project/Area Number: 26830064
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Tumor biology
• Research Institution: Tohoku University
• Principal Investigator: Funayama Ryo 東北大学, 医学(系)研究科(研究院), 助教 (20452295)
• Research Collaborator: NAKAYAMA Keiko 東北大学, 大学院医学系研究科, 教授 (60294972) ; NAGASHIMA Takeshi 東北大学, 大学院医学系研究科, 助教 (80443000) ; HOSOGANE Masaki 東北大学, 大学院医学系研究科, 助手 (30734347)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 転写 / エピジェネティクス / RAS / サイレンシング / shRNA / スクリーニング

Outline of Final Research Achievements

Cancer is caused by DNA mutations. Some mutations cause alterations in gene expression, which result in abnormal growth and viability in cancer cells. We uncovered the molecular mechanism of transcriptional repression induced by an oncogenic RAS mutation, one of the most recurrent mutation in cancer. Phosphorylation activity of protein kinase Erk2 is required for RAS-induced transcriptional repression. Moreover, transcriptional repression triggers alteration of chromatin environment including histone modification.

Research Products

• [Journal Article] Human genetic variation database, a reference database of genetic variations in the Japanese population. (2016)
  • Author(s): Higasa K, Miyake N, Yoshimura J, Okamura K, Niihori T, Saitsu H, Doi K, Shimizu M, Nakabayashi K, Aoki Y, Tsurusaki Y, Morishita S, Kawaguchi T, Migita O, (中略), Matsumoto N, Matsuda F.
  • Journal Title: J Hum Genet. Volume: advance online publication Issue: 6 Pages: 547-553
  • DOI: 10.1038/jhg.2016.12
  • Peer Reviewed / Open Access
• [Journal Article] Genomewide approaches for BACH1 target genes in mouse embryonic fibroblasts showed BACH1-Pparg pathway in adipogenesis. (2016)
  • Author(s): Matsumoto M, Kondo K, Shiraki T, Brydun A, Funayama R, Nakayama K, Yaegashi N, Katagiri H, Igarashi K.
  • Journal Title: Genes Cells. Volume: in press Issue: 6 Pages: 553-567
  • DOI: 10.1111/gtc.12365
  • Peer Reviewed / Open Access
• [Journal Article] The expression of miR-125b-5p is increased in the serum of patients with chronic hepatitis B infection and inhibits the detection of hepatitis B virus surface antigen. (2016)
  • Author(s): Ninomiya M, Kondo Y, Kimura O, Funayama R, Nagashima T, Kogure T, Morosawa T, Tanaka Y, Nakayama K, Shimosegawa T.
  • Journal Title: J Viral Hepat. Volume: in press Issue: 5 Pages: 330-9
  • DOI: 10.1111/jvh.12522
  • Peer Reviewed
• [Journal Article] The artificial loss of Runx1 reduces the expression of quiescence-associated transcription factors in CD4(+) T lymphocytes. (2015)
  • Author(s): Wong WF, Kohu K, Nagashima T, Funayama R, Matsumoto M, Movahed E, Tan GM, Yeow TC, Looi CY, Kurokawa M, Osato M, Igarashi K, Nakayama K, Satake M.
  • Journal Title: Mol Immunol. Volume: 68 Issue: 2 Pages: 223-33
  • DOI: 10.1016/j.molimm.2015.08.012
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Genomic analysis identifies candidate pathogenic variants in 9 of 18 patients with unexplained West syndrome. (2015)
  • Author(s): Hino-Fukuyo N, Kikuchi A, Arai-Ichinoi N, Niihori T, Sato R, Suzuki T, Kudo H, Sato Y, Nakayama T, Kakisaka Y, Kubota Y, Kobayashi T, Funayama R, Nakayama K, Uematsu M, Aoki Y, Haginoya K, Kure S.
  • Journal Title: Hum Genet. Volume: 134 Issue: 6 Pages: 649-658
  • DOI: 10.1007/s00439-015-1553-6
  • Peer Reviewed / Open Access
• [Journal Article] Mutations in MECOM, Encoding Oncoprotein EVI1, Cause Radioulnar Synostosis with Amegakaryocytic Thrombocytopenia. (2015)
  • Author(s): Niihori T, Ouchi-Uchiyama M, Sasahara Y, Kaneko T, Hashii Y, Irie M, Sato A, Saito-Nanjo Y, Funayama R, Nagashima T, Inoue S, Nakayama K, Ozono K, Kure S, Matsubara Y, Imaizumi M, Aoki Y.
  • Journal Title: Am J Hum Genet. Volume: 97 Issue: 6 Pages: 848-854
  • DOI: 10.1016/j.ajhg.2015.10.010
  • Peer Reviewed / Open Access
• [Journal Article] Mutations in PIGL in a patient with Mabry syndrome. (2015)
  • Author(s): Fujiwara I, Murakami Y, Niihori T, Kanno J, Hakoda A, Sakamoto O, Okamoto N, Funayama R, Nagashima T, Nakayama K, Kinoshita T, Kure S, Matsubara Y, Aoki Y.
  • Journal Title: Am J Med Genet A. Volume: in press Issue: 4 Pages: 777-785
  • DOI: 10.1002/ajmg.a.36987
  • Peer Reviewed / Open Access
• [Journal Article] GNE myopathy associated with congenital thrombocytopenia: a report of two siblings. (2014)
  • Author(s): Izumi R, Niihori T, Suzuki N, Sasahara Y, Nishiyama A, Nishiyama S, Endo K, Kato M, Warita H, Konno H, Tateyama M, Nagashima T, Funayama R, Nakayama K, Kure S, Matsubara Y, Aoki Y, Aoki M.
  • Journal Title: Neuromuscul. Disord. Volume: 24(12) Issue: 12 Pages: 1068-1072
  • DOI: 10.1016/j.nmd.2014.07.008
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] HCV infection enhances Th17 commitment, which could affect the pathogenesis of autoimmune diseases (2014)
  • Author(s): Kondo Y, Ninomiya M, Kimura O, Machida K, Funayama R, Nagashima T, Kobayashi K, Kakazu E, Kato T, Nakayama K, Lai MM, Shimosegawa T.
  • Journal Title: PLoS One Volume: 9(6) Issue: 6 Pages: e98521-e98521
  • DOI: 10.1371/journal.pone.0098521
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] TBX1 Mutation Identified by Exome Sequencing in a Japanese Family with 22q11.2 Deletion Syndrome-like Craniofacial Features and Hypocalcemia. (2014)
  • Author(s): Ogata T*, Niihori T, Tanaka N, Kawai M, Nagashima T, Funayama R, Nakayama K, Nakashim S, Kato F, Fukami M, Aoki Y, Matsubara Y
  • Journal Title: PLoS One Volume: 9 Issue: 3 Pages: e91598-e91598
  • DOI: 10.1371/journal.pone.0091598
  • Peer Reviewed / Open Access
• [Presentation] がん原遺伝子RASによる遺伝子サイレンシングの分子機構の解析. (2015)
  • Author(s): 舟山亮, 細金正樹, 長嶋剛史, 中山啓子.
  • Organizer: 第38回日本分子生物学会年会.
  • Place of Presentation: 神戸コンベンションセンター（兵庫県神戸市）
  • Year and Date: 2015-12-01
• [Presentation] TGF-β刺激によるTFIID構成因子TAF7の分解とその役割の解明. 第38回日本分子生物学会年会. (2015)
  • Author(s): 中川直, 細金正樹, 舟山亮, 中山啓子.
  • Organizer: 第38回日本分子生物学会年会.
  • Place of Presentation: 神戸コンベンションセンター（兵庫県神戸市）
  • Year and Date: 2015-12-01
• [Presentation] H3K27me3修飾パターン形成過程の時系列解析. (2014)
  • Author(s): 細金正樹, 舟山亮, 城田松之,中山啓子
  • Organizer: 第37回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2014-11-27
• [Remarks] がん医学コアセンター 細胞増殖制御分野
  • URL: http://www.devgen.med.tohoku.ac.jp/index.html
• [Patent(Industrial Property Rights)] 免疫沈降用の内部標準分子および免疫沈降方法 (2015)
  • Inventor(s): 五十嵐和彦、舟山亮、ほか5名
  • Industrial Property Rights Holder: 五十嵐和彦、舟山亮、ほか5名
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2015-035734
  • Filing Date: 2015-02-25