細胞の癌化とその抑制における転写因子の役割

2009 Fiscal Year Annual Research Report

• Project/Area Number: 17013017
• Research Institution: Tohoku University
• Principal Investigator: 山本 雅之 Tohoku University, 大学院・医学系研究科, 教授 (50166823)
• Co-Investigator(Kenkyū-buntansha): 清水 律子 東北大学, 大学院・医学系研究科, 教授 (40226262)
• Keywords: 多段階発がん / GATA1 / 白血病幹細胞 / 幹細胞性 / 治療抵抗性

Research Abstract

本研究は、発がん防御という視点に焦点を絞り,転写因子機能を総合的に理解することを目的としている。本年度は、赤血球・巨核球分化に重要なGATA1遺伝子に着目して、その機能破綻が引き起こす白血病発症メカニズム解析に取り組んだ。ダウン症候群患児に高率に発症する一過性骨髄増殖背疾患(TMD)や巨核芽球性白血病(AMKL)の芽球では、ほぼ全例にGATA1のアミノ末端領域を欠失したGATA1(ΔNT-GATA1)が発現している。我々は、ΔNT-GATA1のみを発現する遺伝子改変マウスでは、胎生肝で未熟な巨核芽球が異常蓄積していること、この異常蓄積が出生後の脾臓や骨髄では見られないこと、このマウスは白血病を発症しないことを見いだした。このことは、TMDの発症には21番染色体トリソミーは必須ではなく、Gata1遺伝子の異常のみで病態を構築することができる、しかし、GATA1異常のみではAMKLは発症せず、AMKLの発症にはさらなる遺伝子変異が必要であることを示している。一方我々は先に、GATA1の発現低下を原因とする増殖・分化・アポトーシス制御の破綻により赤血球前駆細胞が異常蓄積し、さらなる遺伝子変異を引き金として白血病を発症することを報告した。これらの解析から、構造異常(アミノ末端欠失)とGATA1の量的異常(発現量低下)とが、それぞれ系列特異的(巨核球、赤血球)前駆細胞の異常蓄積を引き起こすこと(前白血病状態)、しかし、GATA1の単独異常では白血病を発症せず、いずれの場合も白血病発症さらなる遺伝子の異常が引き金となること(白血病の多段階発癌)を明らかにした。

Research Products

• [Journal Article] Loss of the Gata1 gene IE exon leads to variant transcript expression and the production of a GATA1 protein lacking the N-terminal domain (2010)
  • Author(s): Kobayashi E, Shimizu R, Kikuchi Y, Takahashi S, Yamamoto M
  • Journal Title: J Biol Chem 285 Pages: 773-783
• [Journal Article] Suppression of AhR signaling pathway is associated with the down-regulation of UDP-glucurono syltransferases during BBN-induced urinary bladder carcinogenesis in mice (2010)
  • Author(s): Iida K, Itoh K, Mimura J, Ohyama C, Fujii-Kuriyama Y, Shimazui T, Akaza H, Yamamoto M
  • Journal Title: J Biochem 147 Pages: 353-360
  • Peer Reviewed
• [Journal Article] Novel regulation of the Nrf2-Keap1 pathway by the selective autophagy substrate p62 (2010)
  • Author(s): Komatsu M, Kurokawa H, Waqun S, Iaguchi K, Kobayashi A, Ichimura Y, Sou Y-S, Ueno I, Sakamoto A, Tong KI, Kim M, Iemura S, Natsume T, Ueno T, Kominami E, Motohashi H, Tanaka K, Yamamoto M
  • Journal Title: Nature Cell Biol 12 Pages: 213-223
  • Peer Reviewed
• [Journal Article] The transcriptome of Nrf2^<-/-> Mice provides evidence for impaired cell cycle progress ion in the development of cigarette-smoke-induced emphysematous changes (2010)
  • Author(s): Gebel S, Diehl S, Pype J, Friedrichs B, Weiler H, Schuller J, Xu H, Taguchi K, Yamamoto M, Muller T
  • Journal Title: Tox Sci (印刷中)
  • Peer Reviewed
• [Journal Article] Stem cells of GATA1-related leukemia undergo pernicious changes after 5-fluorouracil treatment (2009)
  • Author(s): Abe K, Shimizu R, Pan X, Hamada H, Yoshikawa H, Yamamoto M
  • Journal Title: Exp Hematol 37 Pages: 435-445
• [Journal Article] Induction of hyperproliferative fetal megakaryopoiesis by an N-terminally truncated GATA1 mutant (2009)
  • Author(s): Shimizu R, Kobayashi E, Engel JD, Yamamoto M
  • Journal Title: Genes Cells 14 Pages: 1119-1131
• [Journal Article] The antioxidant defense system Keap1-Nrf2 comprises a multiple sensing mechanism for responding to a wide range of chemical compounds (2009)
  • Author(s): Kobayashi M, Li L, Iwamoto N, Nakajima-Takagi Y, Kaneko H, Nakayama Y, Eguchi M, Wada Y, Kumagai Y, Yamamoto M
  • Journal Title: Mol Cell Biol 29 Pages: 493-502
  • Peer Reviewed
• [Journal Article] Differential contribution of the Gata1 gene hematopoietic enhancer to erythroid differentiation (2009)
  • Author(s): Suzuki M, Moriguchi T, Ohneda K, Yamamoto M
  • Journal Title: Mol Cell Biol 29 Pages: 1163-1175
  • Peer Reviewed
• [Journal Article] Increased Nrf2 activation in Keap1-knockdown mice increases hepatic cytoprotective genes that detoxify electrophiles but not reactive oxygen species (2009)
  • Author(s): Reisman SA, Yeager RL, Yamamoto M, Klaassen CD
  • Journal Title: Tox Sci 108 Pages: 35-47
  • Peer Reviewed
• [Journal Article] Transcription factor Nrf2 mediates an adaptive response to sulforaphane that protects fibroblasts in vitro against the cytotoxic effects of electrophiles, peroxides and redox-cycling agents (2009)
  • Author(s): Higgins LG, Kelleher MO, Eggleston IM, Itoh K, Yamamoto M, Hayes JD
  • Journal Title: Toxicol Appl Pharmacol 237 Pages: 267-280
  • Peer Reviewed
• [Journal Article] Comparison of citrus coumarins on carcinogen-detoxifying enzymes in Nrf2 knockout mice (2009)
  • Author(s): Prince M, Li Y, Childers A, Itoh K, Yamamoto M, Kleiner HE
  • Journal Title: Toxicol Lett 185 Pages: 180-186
  • Peer Reviewed
• [Journal Article] Dietary sulforaphane-rich broccoli sprouts reduce colonization and attenuate gastritis in Helicobacter pylori-infected mice and humans (2009)
  • Author(s): Yanaka A, Fahey JW, Fukumoto A, Nakayama M, Inoue S, Zhang S, Tauchi M, Suzuki H, Hyodo I, Yamamoto M
  • Journal Title: Cancer Prev Res 2 Pages: 353-360
  • Peer Reviewed
• [Journal Article] Genetic versus chemoprotective activation of Nrf2 signaling : overlapping yet distinct gene expression profiles between Keap1 knockout and triterpenoid treated mice (2009)
  • Author(s): Yates MS, Tran QT, Dolan PM, Osburn WO, Shin S, McCulloch CC, Silkworth JB, Taguchi K, Yamamoto M, Williams CR, Liby KT, Sporn MB, Sutter TR, Kensler TW
  • Journal Title: Carcinogenesis 30 Pages: 1024-1031
  • Peer Reviewed
• [Journal Article] Nrf2 enhances cell proliferation and resistance to anticancer drugs in hum an lung cancer (2009)
  • Author(s): Homma S, Ishii Y, Morishima Y, Yamadori T, Matsuno Y, Haraguchi N, Kikuchi N, Satoh H, Sakamoto T, Hizawa N, Itoh K, Yamamoto M
  • Journal Title: Clin Cancer Res 15 Pages: 3423-3432
  • Peer Reviewed
• [Journal Article] 1-Cyano-2, 3-epithiopropane is a novel plant-derived chemopreventive agent which induces cytoprotective genes that afford resistance against the genotoxic{alpha},{beta}-unsaturated aldehyde acrolein (2009)
  • Author(s): Kelleher MO, McMahon M, Eggleston IM, Dixon MJ, Taguchi K, Yamamoto M, Hayes JD
  • Journal Title: Carcinogenesis 30 Pages: 1754-1762
  • Peer Reviewed
• [Journal Article] Targeting Nrf2 with the Triterpenoid CDDO-Imidazolide attenuates cigarette smoke-induced emphysema and cardiac dysfunction in mice (2009)
  • Author(s): Sussan IE, Hangasamy T, Blake DJ, Mainotra U, El-Haddad H, Bedja D, Yates MS, Kombairaju P, Yamamoto M, Liby KT, Sporn MB, Gabrielson KL, Champion HC, Tuder RM, Kensler TW, Biswal S
  • Journal Title: Proc Natl Acad Sci USA 106 Pages: 250-255
  • Peer Reviewed
• [Journal Article] Nrf2 counteracts cholestatic liver injury via stimulation of hepatic defense systems (2009)
  • Author(s): Okada K, Shoda J, Taguchi K, Maher JM, Ishizaki K, Inoue Y, Ohtsuki M, Goto N, Sugimoto H, Utsunomiya H, Oda K, Warabi E, Ishii T, Yamamoto M
  • Journal Title: Biochem Biophys Res Commun 389 Pages: 431-436
  • Peer Reviewed
• [Presentation] Nrf2-Keap1環境応答系機能の分子・構造基盤 (2009)
  • Author(s): 山本雅之
  • Organizer: 蛋白研セミナー「活性酸素のシグナル伝達」
  • Place of Presentation: 大阪
  • Year and Date: 20091127-20091128
• [Presentation] Structural Basis of Nrf2-Keap1 Function (2009)
  • Author(s): 山本雅之
  • Organizer: Dasan 2009 Conferece on Bioremodelling
  • Place of Presentation: Jeju, Korea
  • Year and Date: 20091118-20091120
• [Presentation] The Nrf2-Keap1 System and Cancer (2009)
  • Author(s): 山本雅之
  • Organizer: 20th Asia Pacific Cancer Conference
  • Place of Presentation: つくば
  • Year and Date: 20091112-20091114
• [Presentation] セレン蛋白質とNrf2による酸化ストレスに対する2段階防御 (2009)
  • Author(s): 鈴木隆史、川谷幸恵、Vincent Kelly、山本雅之
  • Organizer: 第82回 日本生化学会
  • Place of Presentation: 神戸
  • Year and Date: 20091021-20091024
• [Presentation] 遺伝子組換え実験および遺伝子組み換え動物モデルと医学研究の発展 (2009)
  • Author(s): Masayuki Yamamoto, Tatsuhiro Shibata, Ohta Tsutomu, Kit Tong, Hirofumi Kurokawa, Takafumi Suzuki, Keiko Taguchi, Hozumi Motohashi
  • Organizer: 第68回 日本癌学会学術総会シンポジウム
  • Place of Presentation: 横浜
  • Year and Date: 20091001-20091003
• [Presentation] Nrf2-Keap1系と発癌 (2009)
  • Author(s): 山本雅之
  • Organizer: 68回 日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 20091001-20091003
• [Presentation] Regulation of erythropoietin gene expression in mouse (2009)
  • Author(s): Masayuki Yamamoto, Xiaoqing Pan, Syun Yamazaki, Ikuo Hirano, Naoko Minegishi, Norio Suzuki
  • Organizer: 8th International Luebeck Conference on the Pathophysiology and Pharmacology of Erythropoietin and other Hemopoietic Growth Factors
  • Place of Presentation: Luebeck, Germany
  • Year and Date: 20090730-20090801
• [Presentation] Roles of HIF-binding sequences in chromatin dynamics during activation of the hypoxia-inducible genes (2009)
  • Author(s): Norio Suzuki, Orjan Wrange, Katarina Gradin, Sergey Belikov, Kian Leong Lee, Masayuki Yamamoto, Lorenz Poellinger
  • Organizer: 8th International Luebeck Conference on the Pathophysiology and Pharmacology of Erythropoietin and other Hemopoietic Growth Factors
  • Place of Presentation: Luebeck, Germany
  • Year and Date: 20090730-20090801
• [Presentation] GATA factor switching during erythroid differentiation (2009)
  • Author(s): Masayuki Yamamoto, Takashi Moriguchi, Mikiko Suzuki, Ritsuko Shimizu
  • Organizer: Gordon Conference on Red Blood Cells
  • Place of Presentation: Biddeford, ME
  • Year and Date: 20090628-20090703
• [Presentation] 含セレン蛋白質とNrf2による2段階生体防御機構 (2009)
  • Author(s): 鈴木隆史、川谷幸恵、Vincent Kelly、山本雅之
  • Organizer: 第62回 日本酸化ストレス学会
  • Place of Presentation: 福岡
  • Year and Date: 20090611-20090612
• [Presentation] Molecular basis for the Nrf2-Keap1 system function (2009)
  • Author(s): 山本雅之
  • Organizer: Experimental Biology 2009
  • Place of Presentation: New Orleans, LA, USA
  • Year and Date: 20090418-20090422
• [Presentation] 酸化ストレス応答と病態 (2009)
  • Author(s): 山本雅之
  • Organizer: 第7回 Vascular and Brain Conference
  • Place of Presentation: 大阪
  • Year and Date: 20090403-20090404
• [Presentation] Molecular Basis of Oxidative Stress Response (2009)
  • Author(s): 山本雅之
  • Organizer: International Symposium on Inflammation and Redox Signaling
  • Place of Presentation: Culture Center, Seoul National University
  • Year and Date: 2009-11-21
• [Presentation] The Nrf2-Keap1 system and cancer chemoprevention (2009)
  • Author(s): 山本雅之
  • Organizer: Special seminar at the Korean Society of Cancer Prevention, Lee Gil Ya Cancer and Diabetes Institute
  • Place of Presentation: Incheon, Korea
  • Year and Date: 2009-11-20
• [Presentation] エリスロポエチンの産生細胞と発現制御 (2009)
  • Author(s): 山本雅之
  • Organizer: 5回長時間透析研究会ランチョンセミナー
  • Place of Presentation: 横浜
  • Year and Date: 2009-11-08
• [Presentation] エリスロポエチン遺伝子の発現調節メカニズム (2009)
  • Author(s): 山本雅之
  • Organizer: 第18回 腎とエリスロポエチン研究会
  • Place of Presentation: 東京
  • Year and Date: 2009-11-07
• [Presentation] 環境応答転写因子群と炎症・アレルギー (2009)
  • Author(s): 山本雅之
  • Organizer: 第59回 日本アレルギー学会秋季学術大会 特別企画シンポジウム2
  • Place of Presentation: 秋田
  • Year and Date: 2009-10-29
• [Presentation] Mouse Models of GATA1-related Leukemia (2009)
  • Author(s): 山本雅之
  • Organizer: 14th International Association for Comparative Research on Leukemia, Related Diseases
  • Place of Presentation: Comprehensive Cancer Center, The Ohio State University
  • Year and Date: 2009-10-14
• [Presentation] The Nrf2-Keap1 System and Environmental Stress Response (2009)
  • Author(s): 山本雅之
  • Organizer: Kansas University
  • Place of Presentation: Kansas, USA
  • Year and Date: 2009-10-12
• [Presentation] Nrf2-Keap1システムと肺疾患 (2009)
  • Author(s): 山本雅之
  • Organizer: 第12回 質性肺炎細胞分子病態研究会「慢性炎症機序と呼吸器疾患」
  • Place of Presentation: 東京
  • Year and Date: 2009-08-22
• [Presentation] The Nrf2-Keap1 system and oxidative stress response (2009)
  • Author(s): 山本雅之
  • Organizer: International Symposium 2009 on Signaling Functions of Reactive Oxygen Species
  • Place of Presentation: Aso, Kumamoto
  • Year and Date: 2009-07-18
• [Presentation] 環境適応・応答の分子機構 (2009)
  • Author(s): 山本雅之
  • Organizer: 第18回 翠嶂会・近畿大学大学院医学研究科 ハイテクリサーチセンター合同公開シンポジウム「ヒト疾患モデル研究の新展開」
  • Place of Presentation: 大阪
  • Year and Date: 2009-07-15
• [Presentation] Nrf2-Keap1系の分子構造基盤と発癌 (2009)
  • Author(s): 山本雅之
  • Organizer: 9回 日本蛋白質科学会年会シンポジウム
  • Place of Presentation: 熊本
  • Year and Date: 2009-05-20
• [Remarks]
  • URL: http://dmbc.med.tohoku.ac.jp/official/index.html