Roles of transcription factors for carcinogenesis and carcinogenesisdefense

2009 Fiscal Year Final Research Report

• Project/Area Number: 17013017
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Tohoku University (2007-2009); University of Tsukuba (2005-2006)
• Principal Investigator: MASAYUKI Yamamoto Tohoku University, 大学院・医学系研究科, 教授 (50166823)
• Co-Investigator(Kenkyū-buntansha): RITSUKO Shimizu 東北大学, 大学院・医学系研究科, 教授 (40226262) ; KINUKO Ohneda 高崎健康福祉大学, 薬学部・薬学科, 教授 (50323291)
• Project Period (FY): 2005 – 2009
• Keywords: 転写因子 / 発癌 / 癌抑制

Research Abstract

In this study, we investigated roles transcription factors play on carcinogenesis and carcinogenesis defense in vivo, focusing on the Nrf2 and GATA transcription factors. We have found that co-operative function of Nrf2 and Keap1, which mediates cellular stress response, is important for the cancer carcinogenesis defense so that the failure in Nrf2-Keap1 system leads to the onset of cancer and poor prognosis. We have further found that deregulated function of GATA factors, which act as key molecules in hematopoietic homeostasis, causes leukemogenesis.

Research Products

• [Journal Article] Novel regulation of the Nrf2-Keap1 pathway by the selective autophagy substrate p62 (2010)
  • Author(s): Komatsu M, Kurokawa H, Waguri S, Taguchi 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] Genetic analysis of hierarchical regulation for Gata1 and NF-E2 p45 gene expression in megakaryopoiesis (2010)
  • Author(s): Takayama M, Fujita R, Suzuki M, Okuyama R, Aiba S, Motohashi H, Yamamoto M
  • Journal Title: Mol Cell Biol 12 Pages: 3016-3026
• [Journal Article] Genetic analysis of cytoprotective functions supported by graded expression of Keap1 (2010)
  • Author(s): Taguchi K, Maher JM, Suzuki T, Kawatani Y, Motohashi H, Yamamoto M
  • Journal Title: Mol Cell Biol
• [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] NF-E2 domination over Nrf2 promotes ROS accumulation and megakaryocytic maturation (2010)
  • Author(s): Motohashi H, Kimura M, Fujita R, Takayama M, Pan XQ, Katsuoka F, Aburatani H, Bresnick EH, Yamamoto M
  • Journal Title: Blood 115 Pages: 677-686
• [Journal Article] Keap1 homodimer is a forked-stem structure with two large spheres enclosing the intervening, double glycine repeat, and C-terminal domains (2010)
  • Author(s): Ogura T, Tong KI, Mio K, Maruyama Y, Kurokawa H, Sato C, Yamamoto M
  • Journal Title: Proc Natl Acad Sci USA 107 Pages: 2842-2847
• [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
• [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] Direct binding of pRb/E2F-2 to GATA-1 regulates maturation and terminal cell division during erythropoiesis (2009)
  • Author(s): Kadri Z, Shimizu R, Ohneda O, Maouche-Chretien L, Gisselbrecht S, Yamamoto M, Romeo PH, Leboulch P, Chretien S
  • Journal Title: PLoS Biol 7 Pages: e1000123
• [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] Structural basis of alternative DNA recognition by Maf transcription factors (2009)
  • Author(s): Kurokawa H, Motohashi H, Sueno S, Kimura M, Takagawa H, Kanno Y, Yamamoto M, Tanaka T
  • Journal Title: Mol Cell Biol 29 Pages: 6232-6244
• [Journal Article] Deletion of the selenocysteine tRNA gene in macrophage and liver results in compensatory gene induction of cytoprotective enzymes by Nrf2 (2008)
  • Author(s): Suzuki T, Kelly VP, Motohashi H, Nakajima O, Takahashi S, Nishimura S, Yamamoto M
  • Journal Title: J Biol Chem 283 Pages: 2021-2030
• [Journal Article] Molecular evolution of Keap1: Two Keap1 molecules with distinctive IVR structures are conserved among fish (2008)
  • Author(s): Li L, Kobayashi M, Kaneko H, Nakajima-Takagi Y, Nakayama Y, Yamamoto M
  • Journal Title: J Biol Chem 283 Pages: 3248-3255
• [Journal Article] Physiological significance of reactive cysteine residues of Keap1 in determining Nrf2 activity (2008)
  • Author(s): Yamamoto T, Suzuki T, Kobayashi A, Wakabayashi J, Maher J, Motohashi H, Yamamoto M
  • Journal Title: Mol Cell Biol 28 Pages: 2758-2770
• [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, Hirohashi S
  • Journal Title: Proc Natl Acad Sci USA 105 Pages: 13568-13573
• [Journal Article] NRF1 and NRF2 play distinct roles in activation of antioxidant response element-dependent genes (2008)
  • Author(s): Ohtsuji M, Katsuoka F, Kobayashi A, Aburatani H, Hayes JD, Yamamoto M
  • Journal Title: J Biol Chem 283 Pages: 33554-33562
• [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, Yamada A, Takeuchi M, Yamagishi S, Morito N, Nakano T, Ojima M, Shimohata H, Itoh K, Takahashi S, Yamamoto M
  • Journal Title: Genes Cells 13 Pages: 1159-1170
• [Journal Article] GATA1-related leukaemias (2008)
  • Author(s): Shimizu R, Engel JD, Yamamoto, M.
  • Journal Title: Nature Reviews Cancer 8 Pages: 279-287
• [Journal Article] Nrf2 Neh5 domain is differentially utilized in the transactivation of cytoprotective genes (2007)
  • Author(s): Zhang J, Hosoya T, Maruyama A, Nishikawa K, Maher JM, Ohta T, Motohashi H, Fukamizu A, Shibahara S, Itoh K, Yamamoto M
  • Journal Title: Biochem J 404 Pages: 459-466
• [Journal Article] Enhanced spontaneous and benzo[a]pyrene- induced mutations in the lung of Nrf2-deficient gpt delta mice (2007)
  • Author(s): Aoki Y, Hashimoto AH, Amanuma K, Matsumoto M, Hiyoshi K, Takano H, Masumura K, Itoh K, Nohmi T, Yamamoto M
  • Journal Title: Cancer Res 67 Pages: 5643-5648
• [Journal Article] Nrf2 and p53 cooperatively protect against BBN-induced urinary bladder carcinogenesis (2007)
  • Author(s): Iida K, Itoh K, Maher JM, Kumagai Y, Oyasu R, Mori Y, Fukushima S, Shimazui T, Akaza H, Yamamoto M
  • Journal Title: Carcinogenesis 28 Pages: 2398-2403
• [Journal Article] Different electrostatic potentials define ETGE and DLG motifs as hinge and latch in oxidative stress response (2007)
  • Author(s): Tong KI, Padmanabhan B, Kobayashi A, Shang C, Hirotsu Y, Yokoyama S, Yamamoto M
  • Journal Title: Mol Cell Biol 27 Pages: 7511-7521
• [Journal Article] Subcellul localization and cytoplasmic complex status of endogenous Keap1 (2007)
  • Author(s): Watai Y, Kobayashi A, Nagase H, Mizukami M, McEvoy J, Singer JD, Itoh K, Yamamoto M
  • Journal Title: Genes Cells 12 Pages: 1163-1178
• [Journal Article] Potential involvement of pathophysiologically formed 8-nitorguanosine 3', 5'-cyclic monophosphate in nitric oxide-induced signal transduction (2007)
  • Author(s): Sawa T, Zaki MH, Okamoto T, Akuta T, Tokutomi Y, Kim-Mitsuyama S, Ihara H, Kobayashi A, Yamamoto M, Fujii S, Arimoto H, Akaike T
  • Journal Title: Nature Chem Biol 3 Pages: 727-735
• [Journal Article] Loss of p62/SQSTM1 suppresses cytoplasmic inclusion body formation and liver injury in autophagy-deficient mouse (2007)
  • Author(s): Komatsu M, Waguri S, Koike M, Sou Y, Ueno T, Hara T, Mizushima N, Iwata J, Ezaki J, Murata S, Hamazaki J, Nishito Y, Iemura S, Natsume T, Yanagawa T, Uwayama J, Warabi E, Yoshida H, Ishii T, Kobayashi A, Yamamoto M, Yue Z, Uchiyama Y, Kominami E, Tanaka K
  • Journal Title: Cell 131 Pages: 1149-1163
• [Journal Article] Molecular basis distinguishing the DNA binding profile of NRF2-MAF heterodimer from that of MAF homodimer (2007)
  • Author(s): Kimura M, Yamamoto T, Zhang J, Itoh K, Kyo M, Kamiya T, Aburatani H, Katsuoka F, Kurokawa H, Tanaka T, Motohashi H, Yamamoto M
  • Journal Title: J Biol Chem 282 Pages: 33681-33690
• [Journal Article] Carcinogenesis and transcriptional regulation through Maf recognition elements (2007)
  • Author(s): Motohashi H, Yamamoto M
  • Journal Title: Cancer Sci 98 Pages: 135-139
• [Journal Article] Oxidative and electrophilic stresses activate Nrf2 through inhibition of ubiquitination activity of Keap1 (2006)
  • Author(s): Kobayashi A, Kang MI, Watai Y, Tong KI, Shibata T, Uchida K, Yamamoto M
  • Journal Title: Mol Cell Biol 26 Pages: 221-229
• [Journal Article] Structural basis for defects of Keap1 activity provoked by its point mutations in lung cancer (2006)
  • Author(s): Padmanabhan B, Tong KI, Ohta T, Nakamura Y, Scharlock M, Ohtsuji M, Kang M-I, Kobayashi A, Yokoyama S, Yamamoto M
  • Journal Title: Mol Cell 21 Pages: 689-700
• [Journal Article] Keap1 recruits Neh2 through binding to ETGE and DLG motifs: characterization of the two-site molecular recognition model (2006)
  • Author(s): Tong KI, Katoh Y, Kusunoki H, Itoh K, Tanaka T, Yamamoto M
  • Journal Title: Mol Cell Biol 26 Pages: 2887-2900
• [Journal Article] Predictive base substitution rules that determine the binding and transcriptional specificity of Maf recognition elements (2006)
  • Author(s): Yamamoto T, Kyo M, Kamiya T, Tanaka T, Engel JD, Motohashi M, Yamamoto M
  • Journal Title: Genes Cells 11 Pages: 575-591
• [Journal Article] MafG sumoylation is required for active transcriptional repression (2006)
  • Author(s): Motohashi H, Katsuoka F, Miyoshi C, Uchimura Y, Saitoh H, Francastel C, Engel JD, Yamamoto M
  • Journal Title: Mol Cell Biol Pages: 4652-4663
• [Journal Article] BRG1 Interacts with Nrf2 to selectively mediate HO-1 induction in response to oxidative stress (2006)
  • Author(s): Zhang J, Ohta T, Maruyama A, Hosoya T, Nishikawa K, Maher JM, Shibahara S, Itoh K, Yamamoto M
  • Journal Title: Mol Cell Biol 26 Pages: 7942-7952
• [Journal Article] Nrf2-Keap1 regulation of cellular defense mechanisms against electrophiles and reactive oxygen species (2006)
  • Author(s): Kobayashi M, Yamamoto M
  • Journal Title: Adv Enz Regl Elsevier Science B.V., New York vol.46 Pages: 113-140
• [Journal Article] Two-site substrate recognition model for the Keap1-Nrf2 System: a hinge and latch mechanism (2006)
  • Author(s): Tong KI, Kobayashi A, Katsuoka F, Yamamoto M
  • Journal Title: Biol Chem 387 Pages: 1311-1320
• [Journal Article] Nrf2 transcriptionally activates the mafG gene through an antioxidant response element (2005)
  • Author(s): Katsuoka F, Motohashi M, Engel JD, Yamamoto M
  • Journal Title: J Biol Chem 280 Pages: 4483-4490
• [Journal Article] Pi class glutathione S-transferase genes are regulated by Nrf2 through an evolutionarily conserved regulatory element in zebrafish (2005)
  • Author(s): Suzuki T, Takagi Y, Osanai H, Li L, Takeuchi M, Katoh Y, Kobayashi M, Yamamoto M
  • Journal Title: Biochem J 388 Pages: 65-73
• [Journal Article] The distal sequence element of the selenocysteine tRNA gene is a tissue-dependant enhancer essential for mouse embryogenesis (2005)
  • Author(s): Kelly VP, Suzuki T, Nakajima O, Arai T, Tamai Y, Takahashi S, Nishimura S, Yamamoto M
  • Journal Title: Mol Cell Biol 25 Pages: 3658-3669
• [Journal Article] Differential responses of the Nrf2-Keap1 system to laminar and oscillatory shear stresses in endothelial cells (2005)
  • Author(s): Hosoya T, Maruyama A, Kang M-i, Kawatani Y, Shibata T, Uchida K, Itoh K, Yamamoto M
  • Journal Title: J Biol Chem 280 Pages: 27244-27250
• [Journal Article] Genetic evidence that small Maf proteins are essential for the activation of antioxidant response element-dependent genes (2005)
  • Author(s): Katsuoka F, Motohashi H, Ishii T, Aburatani H, Engel JD, Yamamoto M
  • Journal Title: Mol Cell Biol 25 Pages: 8044-8051
• [Journal Article] Constitutive expression of aryl hydrocarbon receptor in keratinocytes causes inflammatory skin lesions (2005)
  • Author(s): Tauchi M, Hida A, Negishi T, Katsuoka F, Noda S, Mimura J, Hosoya H, Yanaka A, Aburatani H, Fujii-Kuriyama Y, Motohashi H, Yamamoto M
  • Journal Title: Mol Cell Biol 25 Pages: 9360-9368
• [Journal Article] Nrf2-deficient mice are highly susceptible to cigarette smoke-induced emphysema (2005)
  • Author(s): Iizuka T, Ishii Y, Itoh K, Kiwamoto T, Kimura T, Matsuno Y, Morishima Y, Hegab AE, Homma S, Nomura A, Sakamoto T, Shimura M, Yoshida A, Yamamoto M, Sekizawa K
  • Journal Title: Genes Cells 10 Pages: 1113-1125
• [Journal Article] Role of the nrf-2 gene in protection and repair of gastric mucosa against oxidative stress (2005)
  • Author(s): Yanaka A, Zhang S, Tauchi M, Suzuki H, Shibahara T, Matsui H, Nakahara A, Tanaka N, Yamamoto M
  • Journal Title: Inflammopharmacology 13 Pages: 83-90
• [Journal Article] Molecular mechanisms activating Nrf2-Keap1 pathway in regulation of antioxidant genes (2005)
  • Author(s): Kobayashi M, Yamamoto M
  • Journal Title: Antioxidants Redox Signaling 7 Pages: 384-395
• [Remarks]
  • URL: http://dmbc.med.tohoku.ac.jp/official/index.html