細胞の癌化とその制御における転写因子の役割

2008 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 筑波大学, 大学院・人間総合科学研究科, 講師 (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、GATA1分子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という、多段階白血病発症モデル系がすでに確立しているGatal遺伝子ノックダウンマウスヘテロ接合体をツールとして白血病発症メカニズムの解明に取り組んだ。Gatal遺伝子ノックダウンマウスヘテロ接合体に発症する白血病には白血病幹細胞(LSC)が存在し、Hoechst染色陰性のSP分画に濃縮されていることを見いだした。LSC細胞は、造血幹細胞(HSC)の幹細胞性に関与すると報告されているいくつかの遺伝子を発現している一方で、赤血球前駆細胞特有の遺伝子も発現していることから、異常蓄積した赤血球前駆細胞が幹細胞性を獲得して白血病化したと考えられる。また、LSCは、HSCと同様に通常は静止期に存在し、抗がん剤治療に抵抗性であった。LSCはHSCと同様に抗がん剤治療からの回復期に細胞周期にはいり、すみやかに元の白血病状態に再燃する母体となった。ところが、HSCとは異なり、ひとたび細胞周期に入ったLSCは、もとの白血病状態に至っても二度と静止期には戻らず、増殖を続けていた。ヒト白血病の再発症例が初発時の病態に比べて悪性度が増しているという事象は臨床的によく経験されるが、以上の結果から、この原因の一端に治療抵抗性で残存した白血病幹細胞自体の悪性化が関与している可能性が考えられる。

Research Products

• [Journal Article] Nrf2-dependent sulfiredoxin-1 expression protects against cigarette smoke-induced oxidative stress in lungs (2009)
  • Author(s): Singh A, Ling G, Suhasini AN, Z hang P, Yamamoto M, Navas-Acien A, Cosgrove G, Tuder RM, Kensler TW, Watson WH, Biswal S
  • Journal Title: Free Radic Biol Med 46 Pages: 376-386
  • 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, and Yamamoto M
  • Journal Title: Exp Hematol 37 Pages: 435-445
  • Peer Reviewed
• [Journal Article] Increased Nrf2 activation in Keapl-knockdown mice increases hepatic cyto protective genes that detoxify electrophiles but not reactive oxygen species (2009)
  • Author(s): Reisman SA, Yeager RL, Yamamoto M, and Klaassen CD
  • Journal Title: Tox Sci 108 Pages: 35-47
  • Peer Reviewed
• [Journal Article] Leukemia-related transcription factor TEL/ETV6 expands erythroid precursors and stimulates hemoglobin synthesis. (2009)
  • Author(s): Eguchi-lshimae M, Eguchi M, Maki K, Porcher C, Shimizu R, Yamamoto M, and Mitani K
  • Journal Title: Cancer Sci 100 Pages: 689-697
  • Peer Reviewed
• [Journal Article] Impairment of erythroid and megakaryocytic differentiation by a leukemia-associated and t(9 ; 9)-derived fusion gene product, SET/TAF-IB-CAN/Nup214 (2008)
  • Author(s): Saito S, Nouno K, Shimizu R, Yamamoto M, and Nagata K
  • Journal Title: J Cell Physiol 214 Pages: 322-333
  • Peer Reviewed
• [Journal Article] Loss of Keap 1 function activates Nrf2 and provides advantages for lung cancer cells growth (2008)
  • Author(s): Ohta T, Iijima K, Miyamoto M, Nakahara I, Odagawa R, Mimaki S, Sakiyama T, Tanaka H, Ohtsuji M, Suzuki T, Kobayashi A, Shibata T, Yamamoto M, and Hirohashi S
  • Journal Title: Cancer Res 68 Pages: 1303-1309
  • Peer Reviewed
• [Journal Article] Induction of cancer chemopreventive enzymes by coffee is mediated by transcription factor Nrf2. Evidence that the coffee-specific diterpenes cafestol and kahweol confer protection against acrolein (2008)
  • Author(s): Higgins LG, Cavin C, Itoh K, Yamamoto M, and Hayes JD
  • Journal Title: Toxicol Appl Pharmacol 226 Pages: 328-337
  • Peer Reviewed
• [Journal Article] Attenuation of UVB-induced sunburn reaction and oxidative DNA damage with no alterations in UVB-induced skin carcinogenesis in Nrf2 gene-deficient mice (2008)
  • Author(s): Kawachi Y, Xu X, Taguchi S, Sakurai H, Nakamura Y, Ishii Y, Fujisawa Y, Furuta J, Takahashi T, Itoh K, Yamamoto M, Yamazaki F, and Otsuka F
  • Journal Title: J Invest Dermatol 128 Pages: 1773-1779
  • Peer Reviewed
• [Journal Article] Nrf2 mediates cancer protection but not prolongevity induced by caloric restriction (2008)
  • Author(s): Pearson KJ, Lewis KN, Price NL, Chang JW, Perez E, Cascajo M V, Tamashiro KL, Poosala S, Csiszar A, Ungvari Z, Kensler TW, Yamamoto M, Egan JM, Longo DL, Ingram DK, Navas P, de Cabo R
  • Journal Title: Proc Nati Acad Sci USA 105 Pages: 2325-2330
  • Peer Reviewed
• [Journal Article] Ephrin-A1 promotes the malignant progression of intestinal tumors in Apc-mice (2008)
  • Author(s): Shi L, Itoh F, Itoh S, Takahashi S, Yamamoto M, and Kato M
  • Journal Title: Oncogene 27 Pages: 3265-3273
  • Peer Reviewed
• [Journal Article] Ablation of Gata1 in adult mice results in aplastic crisis, revealing its essential role in steady state and stress erythropoiesis (2008)
  • Author(s): Gutierrez L, Tsukamoto S, Suzuki M, Yamamoto-Mukai H, Yamamoto M, Philipsen S, and Ohneda K
  • Journal Title: Blood 111 Pages: 4375-4385
  • Peer Reviewed
• [Journal Article] Differential roles for Nrf2 and AP-1 in upregulation of HO-1 expression by arsenite in murine embryonic fibroblasts (2008)
  • Author(s): Harada H, Sugimoto R, Watanabe A, Taketani S, Okada K, Warabi E, Siow R, Itoh K, Yamamoto M, and Ishii T
  • Journal Title: Free Radical liesearcn 42 Pages: 297-304
  • Peer Reviewed
• [Journal Article] Redox cycling of 9,10-phenanthraquinone to cause oxidative stress is terminated through its monoglucuronide conjugation in human pulmonary epithelial A549 cells (2008)
  • Author(s): Taguchi K, Shimada M, Fujii S, Sumi D, Pan X, Yamano S, Nishiy ama T, Hiratsuka A, Yamamoto M, Cho AK, Froines JR, and Kumagai Y
  • Journal Title: Free Radic Biol Med 44 Pages: 1645-1655
  • Peer Reviewed
• [Journal Article] Activation of nuclear factor E2-related factor 2 in hereditary tyrosinemia type 1 and its role in survival and tumor development (2008)
  • Author(s): Marhenke S, Lamle J, Buitrago-Molina LE, Canon JM, Geffers R, Finegold M, Sporn M, Yamamoto M, Manns MP, Grompe M, and Vogel A
  • Journal Title: Hepatology 48 Pages: 487-496
  • Peer Reviewed
• [Journal Article] A possible role of Nrf2 in prevention of renal oxidative damage by ferric nitrilotriacetate (2008)
  • Author(s): Kanki K, Umemura T, Kitamura Y , Ishii Y, Kuroiwa Y, Kodama Y, Itoh K, Yamamoto M, Nishikawa A. and Hirose M
  • Journal Title: Toxicol Pathol 36 Pages: 353-361
  • Peer Reviewed
• [Journal Article] Structural insights into the similar modes of Nrf2 transcription factor recognition by the cytoplasmic repressor Keap 1 (2008)
  • Author(s): Padmanabhan B, Tong KI, Kobay ashi A, Yamamoto M, and Yokoyama S
  • Journal Title: J Synchrotron Radiat 15(Pt3) Pages: 273-276
  • Peer Reviewed
• [Journal Article] Genetic or pharmacologic amplification of Nrf2 signaling inhibits acute intiammatory liver injury in mice (2008)
  • Author(s): Osburn WO, Yates MS, Dolan PD Liby KT, Sporn MB, Taguchi K, Yamamoto M, and Kensler T
  • Journal Title: Toxicol Sci 104 Pages: 218-227
  • Peer Reviewed
• [Journal Article] The transcription factor Nrf2 is a therapeutic target against brain intlammation (2008)
  • Author(s): Innamorato NG, Rojo Al, Garcia-Yagile kJ, Yamamoto M, de Ceballos ML. and Cuadrado A
  • Journal Title: J Immunol 181 Pages: 680-689
  • Peer Reviewed
• [Journal Article] Nuclear Factor E2-Related Factor 2-dependent myocardiac cytoprotection against oxidative and electrophilic stress (2008)
  • Author(s): Zhu H, Jia Z, Misra BR, Zhang L , Cao Z, Yamamoto M, Trush M A, Misra HP, and Li Y
  • Journal Title: Cardiovasc Toxicol 8 Pages: 71-85
  • Peer Reviewed
• [Journal Article] Disruption of Nrf2 enhances susceptibility to airway inflammatory responses induced by low-dose diesel exhaust particles in mice (2008)
  • Author(s): Li YJ, Takizawa H, Azuma A, Kohyama T, Yamauchi Y, Takahashi S, Yamamoto M, Kawada T, Kudoh S. and Suaawara I
  • Journal Title: Clin Immunol 128 Pages: 366-373
  • Peer Reviewed
• [Journal Article] Activation of nuclear factor E2-related factor 2 in hereditary tyrosinemia type 1 and its role in survival and tumor development (2008)
  • Author(s): Marhenke S, Lamle J, Buitrago-M olina LE, Cali& JM, Geffers R, Finegold M, Sporn M, Yamamoto M, Manns MP, Grompe M, and Vogel A
  • Journal Title: Hepatology 48 Pages: 487-496
  • Peer Reviewed
• [Journal Article] Genetic alteration of Keap1 confers constitutive Nrf2 activation and resistance to chemotherapy in gallbladder cancer (2008)
  • Author(s): Shibata T, Kokubu A, Gotoh M, Ojima H, Ohta T, Yamamoto M, and Hirohashi S
  • Journal Title: Gastroenterology 135 Pages: 1358-1368
  • Peer Reviewed
• [Journal Article] Cancer related mutations in NRF2 impair its recognition by Keap1-Cul3 E3 ligase and promote malignancy (2008)
  • Author(s): Shibata T, Ohta T, Tong KI, Kokubu A, Odogawa R, Tsuta K, Asamura H, Yamamoto M, and Hirohashi S
  • Journal Title: Proc Natl Acad Sci USA 105 Pages: 13568-13573
  • Peer Reviewed
• [Journal Article] Disruption of the transcription factor Nrf2 promotes pro-oxidative dendritic cells that stimulate Th2-like immunoresponsiveness upon activation by ambient particulate matter (2008)
  • Author(s): Williams MA, Rangasamy T, Bauer SM, Killedar S, Karp M, Kensler TW, Yamamoto M, Breysse P, Biswal S, and Georas SN
  • Journal Title: J Immunol 181 Pages: 4545-4159
  • Peer Reviewed
• [Journal Article] Hyperglycemia induces oxidative and nitrosative stress and increases renal functional impairment in Nrf2-deficient mice (2008)
  • Author(s): Yoh K, Hirayama A, Ishizaki K, Y amada A, Takeuchi M, Yamagishi S, Morito N, Nakano T, Ojima M, Shimohata H, Itoh K, Takahashi S, and Yamamoto M
  • Journal Title: Genes Cells 13 Pages: 1159-1170
  • Peer Reviewed
• [Journal Article] GATA1-related leukaemias (2008)
  • Author(s): Shimizu R, Engel JD and Yamamoto, M
  • Journal Title: Nature Reviews Cancer 8 Pages: 279-287
  • Peer Reviewed
• [Journal Article] GATA-1の機能異常と白血病-Leukemogenesis related to GATA-1 mutation- (2008)
  • Author(s): 安倍加奈子・清水律子・山本雅之
  • Journal Title: 日本産婦人科血液学会誌 17 Pages: 1-8
  • Peer Reviewed
• [Journal Article] Nrf2-Keap1制御系から望む呼吸器疾患 (2008)
  • Author(s): 佐藤大希・山本雅之
  • Journal Title: 呼吸 27 Pages: 439-445
  • Peer Reviewed
• [Presentation] Structural basis and cancer-related mutations of the Nrf2-Keapl system (2009)
  • Author(s): Yamamoto M
  • Organizer: John Hopkins University Seminar
  • Place of Presentation: JHU Baltimore, USA
  • Year and Date: 2009-09-17
• [Presentation] The Nrf2-Keap 1 system of oxidative/electrophilic stress response: mechanism and diseases. (2008)
  • Author(s): Tong KI., Yamamoto M
  • Organizer: Joint Annual Meeting of the Molecular Biology Society of Japan and the Japanese Biochemical Society. 2008(BMB2008)
  • Place of Presentation: Kobe Port Island, Japan
  • Year and Date: 20081209-12
• [Presentation] Gata1 Gene Regulation and GATA1-related Leukemia (2008)
  • Author(s): Yamamoto M, Moriguchi T, Suzuki M. and Shimizu R
  • Organizer: The 16th Conference on Hemoglobin Switching Asilomar
  • Place of Presentation: California, USA
  • Year and Date: 20081111-15
• [Presentation] Induction of Hyperproliferative Fetal Megakaryopoiesis by an N-terminally Truncated GATA1 Mutant (2008)
  • Author(s): Shimizu R, Engel JD, and Yamamoto M
  • Organizer: The 16th Conference on Hemoglobin Switching, Asilomar
  • Place of Presentation: California, USA
  • Year and Date: 20081111-15
• [Presentation] The Nrf2-Keap1 System and Cancer (2008)
  • Author(s): Yamamoto M
  • Organizer: AACR conference on "Chemical and Biological Aspect of Inflammation and Cancer"
  • Place of Presentation: JW Marriott Ihilani Resort & Spa at Ko Olina, Hawaii, USA
  • Year and Date: 20081111-15
• [Presentation] The Nrf2-Keapl Stress Response System : Molecular Basis of Adaptive Responses to Food and Oxygen (2008)
  • Author(s): Yamamoto M
  • Organizer: 11-SAC Seminar
  • Place of Presentation: Danilovskaya Hotel, Moscow, Russian
  • Year and Date: 20080922-25
• [Presentation] Structural basis and cancer-related mutations of the Nrf2-Keapl system (2008)
  • Author(s): Yamamoto M
  • Organizer: Scientific Colloquium, PHILIP MORRIS Research Laboratories GmbH
  • Place of Presentation: Koln, Germany
  • Year and Date: 2008-09-26
• [Book] Keap1-Nrf2システムによる酸化ストレス・親電子性物質応答機構「酸化ストレスの医学」 (2008)
  • Author(s): 小林聡・山本雅之
  • Total Pages: 46-61(16)
  • Publisher: 診断と治療社
• [Book] 転写制御とエピジェネティクス-ゲノムでコードに向けて- (2008)
  • Author(s): 鈴木隆史、山本雅之
  • Total Pages: 143-149(7)
  • Publisher: 南山堂