Elucidation of DECODE cycle that regulates homeostasis mediated by protein modification.

2009 Fiscal Year Final Research Report

• Project/Area Number: 17054004
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: University of Tsukuba
• Principal Investigator: FUKAMIZU Akiyoshi University of Tsukuba, 大学院・生命環境科学研究科, 教授 (60199172)
• Co-Investigator(Kenkyū-buntansha): DAITOKU Hiroaki 筑波大学, 大学院・生命環境科学研究科, 講師 (30361314) ; HIROTA Keiko 筑波大学, 大学院・生命環境科学研究科, 助手 (00375370)
• Project Period (FY): 2005 – 2009
• Keywords: 翻訳後修飾 / フォークヘッド転写因子 / リン酸化 / アセチル化 / ユビキチン化 / アルギニンメチル化 / アルギニンメチル化コード / 食シグナル

Research Abstract

We have found the ubiquitin-dependent degradation of the forkhead transcription factor・Foxo1 coupled with the phosphorylation mediated via PKB that is activated by insulin-mediated signaling pathway and set out a new mode of insulin action that affects the fate of protein stabilization. We discovered the reduced affinity to the recognition DNA sequence of Foxo1 acetylated by CBP, leading to gene repression of the target genes and demolished the general concept that acetylation of transcription factors induces gene activation. We also demonstrated the re-activation of Foxo1 deacetylated by NAD^+-dependent Sir2. In the present study, we revealed that acetylated Foxo1 is increasingly phosphorylated by PKB and that Foxo1 is methylated by protein arginine methyltransferase・PRMT1 and then the phosphorylation of Foxo1 by PKB is inhibited by the methylation. Furthermore, we illustrated the apoptosis induction mediated by the increased arginine methylation of Foxo1 by PRMT1 in response to H_2O_2 oxidative stress through the Bim gene activation and proposed a novel arginine methylation code as a cross-talk regulation between methylation and phosphorylation.

Research Products

• [Journal Article] PCAF represses transactivation function of FOXO1 in an acetyltransferase-independent manner. (2010)
  • Author(s): oshimochi K, Daitoku H, Fukamizu A.
  • Journal Title: J. Recept. Transduc. Res. 30 Pages: 43-49
  • Peer Reviewed
• [Journal Article] Regulation of FOXO1-mediated transcription and cell proliferation by PARP-1. Biochem. (2009)
  • Author(s): Sakamaki JI, Daitoku H, Yoshimochi K, Miwa M, Fukamizu A
  • Journal Title: Biophys. Res. Commun. 382 Pages: 497-502
  • Peer Reviewed
• [Journal Article] Angiopoietin-1 induces Kruppel-like factor 2 expression through a phosphoinositide 3-kinase/AKT-dependent activation of myocyte enhancer factor 2. (2009)
  • Author(s): Sako K, Fukuhara S, Minami T, Hamakubo T, Song H, Kodama T, Fukamizu A, Gutkind JS, Koh GY, Mochizuki N.
  • Journal Title: J. Biol. Chem. 284 Pages: 5592-5601
  • Peer Reviewed
• [Journal Article] Foxo1 increases pro-inflammatory gene expression by inducing C/EBPbeta in TNF-alpha-treated adipocytes. (2009)
  • Author(s): Ito Y, Daitoku H, Fukamizu A
  • Journal Title: Biochem. Biophys. Res. Commun. 378 Pages: 290-295
  • Peer Reviewed
• [Journal Article] Arginine methylation of FOXO transcription factors inhibits their phosphorylation by Akt. (2008)
  • Author(s): Yamagata K, Daitoku H, Takahashi Y, Namiki K, Hisatake K, Kako K, Mukai H, Kasuya Y, Fukamizu A
  • Journal Title: Mol. Cell 32 Pages: 221-231
  • Peer Reviewed
• [Journal Article] A combination of HNF-4 and Foxo1 is required for reciprocal transcriptional regulation of glucokinase and glucose-6-phosphatase genes in response to fasting and feeding. (2008)
  • Author(s): Hirota K, Sakamaki JI, Ishida J, Shimamoto Y, Nishihara S, Kodama N, Ohta K, Yamamoto M, Tanimoto K, Fukamizu A
  • Journal Title: J. Biol. Chem. 283 Pages: 32432-32441
  • Peer Reviewed
• [Journal Article] Epigenetic control of rDNA loci in response to intracellular energy status. (2008)
  • Author(s): Murayama A, Ohmori K, Fujimura A, Minami H, Yasuzawa-Tanaka K, Kuroda T, Oie S, Daitoku H, Okuwaki M, Nagata K, Fukamizu A, Kimura K, Shimizu T, Yanagisawa J.
  • Journal Title: Cell 133 Pages: 627-639
  • Peer Reviewed
• [Journal Article] EWS is a substrate of type I protein arginine methyltransferase, PRMT8. (2008)
  • Author(s): Kim JD, Kako K, Kakiuchi M, Park GG, Fukamizu, A.
  • Journal Title: Int. J. Mol. Med. 22 Pages: 309-315
• [Journal Article] FOXO transcription factors in the regulatory networks of longevity. (2007)
  • Author(s): Daitoku H, Fukamizu A.
  • Journal Title: J. Biochem. 141 Pages: 769-774
• [Journal Article] Foxo1 links insulin signaling to C/EBPalpha and regulates gluconeogenesis during liver development. (2007)
  • Author(s): Sekine K, Chen YR, Kojima N, Ogata K, Fukamizu A, Miyajima A.
  • Journal Title: EMBO J. 15 Pages: 3607-3615
  • Peer Reviewed
• [Journal Article] Insulin-like growth factor 1/insulin signaling activates androgen signaling through direct interactions of Foxo1 with androgen receptor. (2007)
  • Author(s): Fan W, Yanase T, Morinaga H, Okabe T, Nomura M, Daitoku H, Fukamizu A, Kato S, Takayanagi R, Nawata H.
  • Journal Title: J. Biol. Chem. 282 Pages: 7329-7338
  • Peer Reviewed
• [Journal Article] Mitogen-activated protein kinases, Erk and p38, phosphorylate and regulate Foxo1. (2007)
  • Author(s): Asada S, Daitoku H, Matsuzaki H, Saito T, Sudo T, Mukai H, Iwashita S, Kako K, Kishi T, Kasuya Y, Fukamizu A.
  • Journal Title: Cell Signal. 19 Pages: 519-527
  • Peer Reviewed
• [Journal Article] Bile acid represses the peroxisome proliferator-activated receptor-gamma coactivator-1 promoter activity in a small heterodimer partner-dependent manner. (2007)
  • Author(s): Yamagata K, Yoshimochi K, Daitoku H, Hirota K, Fukamizu, A.
  • Journal Title: Int. J. Mol. Med. 19 Pages: 751-756
  • Peer Reviewed
• [Journal Article] The LXXLL motif of murine forkhead transcription factor FoxO1 mediates Sirt1-dependent transcriptional activity. (2006)
  • Author(s): Nakae J, Cao Y, Daitoku H, Fukamizu A, Ogawa W, Yano Y, Hayashi Y.
  • Journal Title: J. Clin. Invest. 116 Pages: 2473-2483
  • Peer Reviewed
• [Journal Article] Benfotiamine counteracts glucose toxicity effects on endothelial progenitor cell differentiation via Akt/FoxO signaling. (2006)
  • Author(s): Marchetti V, Menghini R, Rizza S, Vivanti A, Feccia T, Lauro D, Fukamizu A, Lauro R, Federici M.
  • Journal Title: Diabetes 55 Pages: 2231-2237
  • Peer Reviewed
• [Journal Article] Smad3 is acetylated by p300/CBP to regulate its transactivation activity. (2006)
  • Author(s): Inoue Y, Itoh Y, Abe K, Okamoto T, Daitoku H, Fukamizu, A, Onozaki K, Hayashi H.
  • Journal Title: Oncogene 26 Pages: 500-508
  • Peer Reviewed
• [Journal Article] Nutrient control of phosphorylation and translocation of Foxo1 in C57BL/6 and db/db mice. (2006)
  • Author(s): Aoyama H, Daitoku H, Fukamizu, A.
  • Journal Title: Int. J. Mol. Med. 18 Pages: 433-439
  • Peer Reviewed
• [Journal Article] Ileal bile acid-binding protein, functionally associated with the farnesoid X receptor or the ileal bile acid transporter, regulates bile acid activity in the small intestine. (2005)
  • Author(s): Nakahara M, Furuya N, Takagi K, Sugaya T, Hirota K, Fukamizu A, Kanda T, Fujii H, Sato R.
  • Journal Title: J. Biol. Chem. 280 Pages: 42283-42289
  • Peer Reviewed
• [Journal Article] Acetylation of Foxo1 alters its DNA-binding ability and sensitivity to phosphorylation. (2005)
  • Author(s): Matsuzaki H, Daitoku H, Hatta M, Aoyama H, Yoshimochi K, Fukamizu A.
  • Journal Title: Proc. Natl. Acad. Sci. 102 Pages: 11278-11283
  • Peer Reviewed
• [Journal Article] (2005)
  • Author(s): Dateki, M, Horii T, Kasuya Y, Mochizuki R, Nagao Y, Ishida J, Sugiyama F, Tanimoto K, Yagami K, Imai H, Fukamizu A.
  • Journal Title: J. Biol. Chem. 280 Pages: 20503-20508
  • Peer Reviewed
• [Journal Article] Mutation analysis of HNF-4 binding sites in the human glucose- 6-phosphatase promoter. (2005)
  • Author(s): Hirota K, Aoyama H, Fukamizu, A.
  • Journal Title: Int. J. Mol. Med. 15 Pages: 487-490
  • Peer Reviewed
• [Journal Article] Identification of cis-regulatory sequences in the human angiotensinogen gene by transgene coplacement and site-specific recombination. (2005)
  • Author(s): Shimizu T, Oishi T, Omori A, Sugiura A, Hirota K, Aoyama H, Saito T, Sugaya T, Kon Y, Engel JD, Fukamizu A, Tanimoto K.
  • Journal Title: Mol. Cell. Biol. 25 Pages: 2938-2945
  • Peer Reviewed
• [Journal Article] Transcriptional down-regulation through nuclear exclusion of EWS methylated by PRMT1. (2005)
  • Author(s): Araya N, Hiraga H, Kako K, Arao Y, Kato S, Fukamizu A.
  • Journal Title: Biochem. Biophys. Res. Commun. 329 Pages: 653-660
  • Peer Reviewed
• [Remarks]
  • URL: http://akif2.tara.tsukuba.ac.jp/