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Regulation of tumor suppressor RB pathway via ubiquitin system.

Research Project

Project/Area Number 16370060
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Functional biochemistry
Research InstitutionHamamatsu University School of Medicine

Principal Investigator

KITAGAWA Masatoshi  Hamamatsu University School of Medicine, Department of Biochemistry 1, Professor, 医学部, 教授 (50294971)

Co-Investigator(Kenkyū-buntansha) KITAGAWA Kyoko  Hamamatsu University School of Medicine, Department of Biochemistry 1, Research Fellow, 医学部, 助手 (20299605)
UCHIDA Chiharu  Hamamatsu University School of Medicine, Department of Biochemistry 1, Research Fellow, 医学部, 助手 (60223567)
ODA Toshiaki  Hamamatsu University School of Medicine, Department of Biochemistry 1, Associate Professor, 医学部, 助教授 (90126805)
HATTORI Takayuki  Hamamatsu University School of Medicine, Department of Biochemistry 1, Post-doctorial Fellow, 医学部, COE研究員 (50377751)
Project Period (FY) 2004 – 2005
Project Status Completed (Fiscal Year 2005)
Budget Amount *help
¥15,500,000 (Direct Cost: ¥15,500,000)
Fiscal Year 2005: ¥5,300,000 (Direct Cost: ¥5,300,000)
Fiscal Year 2004: ¥10,200,000 (Direct Cost: ¥10,200,000)
KeywordsCell cycle / RB / ubiquitin / プロテアソーム / RBタンパク質 / 癌化 / Mdm2
Research Abstract

Retinoblastoma gene product (pRB) plays critical roles in regulation of the cell cycle and tumor suppression. It is known that downregulation of pRB can stimulate carcinogenesis via abrogation of the pRB pathway, although the mechanism has not been elucidated. In this study, we found that Mdm2, a ubiquitin ligase for p53, promoted ubiquitin-dependent degradation of pRB. pRB was efficiently ubiquitinated by wild-type Mdm2 in vivo as well as in vitro, but other RB family proteins were not. Mutant Mdm2 with a substitution in the RING finger domain showed dominant-negative stabilization of pRB. Both knockout and knockdown of Mdm2 caused accumulation of pRB. Moreover, Mdm2 inhibited pRB-mediated flat formation of Saos-2 cells. Downregulation of pRB expression was correlated with a high level of expression of Mdm2 in human lung cancers. These results suggest that Mdm2 regulates function of pRB via ubiquitin-dependent degradation of pRB.

Report

(3 results)
  • 2005 Annual Research Report   Final Research Report Summary
  • 2004 Annual Research Report
  • Research Products

    (51 results)

All 2006 2005 2004

All Journal Article (49 results) Book (2 results)

  • [Journal Article] Effect of MdmX on Mdm2-mediated downregulation of pRB.2006

    • Author(s)
      Uchida, C et al.
    • Journal Title

      FEBS Letters 560

      Pages: 1753-1758

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Ubiquitin-dependent degradation of adenovirus E1A protein is inhibited by BS69.2006

    • Author(s)
      Isobe, T et al.
    • Journal Title

      Biochem Biophys Res Commun. 340

      Pages: 367-374

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Mdm2-mediated pRB downregulation is involved in carcinogenesis in a p53-independent manner.2006

    • Author(s)
      Miwa, S. et al.
    • Journal Title

      Biochem Biophys Res Commun. 340

      Pages: 54-61

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Immunohistochemical and genetic features of gastric and the metastatic liver GISTs, sequential analyses.2006

    • Author(s)
      Kikuchi, H. et al.
    • Journal Title

      Cancer Sci. 97

      Pages: 127-132

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Effect of MdmX on Mdm2-mediated downregulation of pRB.2006

    • Author(s)
      Uchida, C.
    • Journal Title

      FEBS Letters 560

      Pages: 1753-1758

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Ubiquitin-dependent degradation of adenovirus E1A protein is inhibited by BS69.2006

    • Author(s)
      Isobe, T.
    • Journal Title

      Biochem Biophys Res Commun. 339

      Pages: 367-374

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Mdm2-mediated pRB downregulation is involved in carcinogenesis in a p53-independent manner.2006

    • Author(s)
      Miwa, S.
    • Journal Title

      Biochem Biophys Res Commun. 340

      Pages: 54-61

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Immunohistochemical and geneticfeatures of gastric and the metastatic liver GISTs, sequential analyses.2006

    • Author(s)
      Kikuchi, H.
    • Journal Title

      Cancer Sci. 97

      Pages: 127-132

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Ubiquitin-dependent degradation of adenovirus E1A protein is inhibited by BS69.2006

    • Author(s)
      Isobe, T et al.
    • Journal Title

      Biochem Biophys Res Commun. 339

      Pages: 367-374

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Mdm2-mediated pRB downregulation is involved in carcinogenesis in a p53-independent manner.2006

    • Author(s)
      Miwa, S.et al.
    • Journal Title

      Biochem Biophys Res Commun. 340

      Pages: 54-61

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Immunohistochemical and genetic features of gastric and the metastatic liver GISTs, sequential analyses.2006

    • Author(s)
      Kikuchi, H.et al.
    • Journal Title

      Cancer Sci. 97

      Pages: 127-132

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Enhanced Mdm2 activity inhibits pRB function via ubiquitindependent degradation.2005

    • Author(s)
      Uchida, C et al.
    • Journal Title

      EMBO J. 24

      Pages: 160-169

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Transcriptional induction of Smurf2 ubiquitin ligase by TGF-β.2005

    • Author(s)
      Ohashi, N. et al.
    • Journal Title

      FEBS Letters 579

      Pages: 2557-2563

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Preferences for phosphorylation sites in the retinoblastoma protein of D-Type cyclin-dependent kinases Cdk4 and Cdk6 in vitro.2005

    • Author(s)
      Takaki, T. et al.
    • Journal Title

      J. Biochem.

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] The FWD1/β-TrCP-mediated degra-dation pathway establishes a turning off switch of a Cdc42 guanine nucleotide exchange factor, FGD1.2005

    • Author(s)
      Hayakawa M et al.
    • Journal Title

      Genes to Cells 10

      Pages: 241-251

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Aldehyde dehydrogenase 2 gene targeting mouse lacking enzyme activity shows high acetaldehyde level in blood, brain, and liver after ethanol gavages.2005

    • Author(s)
      Isse, T. et al.
    • Journal Title

      Alcohol Clin Exp Res. 29

      Pages: 1959-1964

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] An essential role for mitochondrial aldehyde dehydrogenase in nitroglycerin bioactivation.2005

    • Author(s)
      Chen, Z. et al.
    • Journal Title

      Proc. Nathl. Acad. Sci. USA 102

      Pages: 12159-12164

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Enhanced Mdm2 activity inhibits pRB function via ubiquitin-dependent degradation.2005

    • Author(s)
      Uchida, C.
    • Journal Title

      EMBO J. 24

      Pages: 160-169

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Transcriptional induction of Smurf2 ubiquitin ligase by TGF-β.2005

    • Author(s)
      Ohashi, N.
    • Journal Title

      FEBS Letters 579

      Pages: 2557-2563

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Preferences for phosphorylation sites in the retinoblastoma protein of D-Type cyclin-dependent kinases, Cdk4 and Cdk6 in vitro.2005

    • Author(s)
      Takaki, T.
    • Journal Title

      J.Biochem. 137

      Pages: 381-386

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] The FWD1/β-TrCP-mediated degradation pathway establishes a turning off switch of a Cdc42 guanine nucleotide exchange factor, FGD1.2005

    • Author(s)
      Hayakawa, M.
    • Journal Title

      Genes to Cells 10

      Pages: 241-251

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Aldehyde dehydrogenase 2 gene targeting mouse lacking enzyme activity shows high acetaldehyde level in blood, brain, and liver after ethanol gavages.2005

    • Author(s)
      Isse, T.
    • Journal Title

      Alcohol Clin Exp Res. 29(11)

      Pages: 1959-1964

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] An essential role for mitochondrial aldehyde dehydrogenase in nitroglycerin bioactivation.2005

    • Author(s)
      Chen, Z.
    • Journal Title

      Proc.Nathl.Acad.Sci.USA 102(34)

      Pages: 12159-12164

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] he FWD1/β-TrCP-mediated degra-dation pathway establishes a turning off switch of a Cdc42 guanine nucleotide exchange factor, FGD1.2005

    • Author(s)
      Makio Hayakawa et al.
    • Journal Title

      Genes to Cells 10

      Pages: 241-251

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Enhanced Mdm2 activity inhibits pRB function via ubiquitin-dependent degradation.2005

    • Author(s)
      Chiharu Uchida et al.
    • Journal Title

      EMBO J. 24

      Pages: 160-169

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Cellular FLIP inhibits b-catenin ubiquitylation and enhances Wntsignaling2004

    • Author(s)
      Naito, M. et al.
    • Journal Title

      Mol. Cell. Biol 24

      Pages: 8418-8427

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Down regulation of Smad7 expression by ubiquitin-dependent degradation contributes to renal fibrosis in obstructivenephropathy in mice2004

    • Author(s)
      Fukasawa H. et al.
    • Journal Title

      Proc. Nathl. Acad. Sci. USA 101

      Pages: 8687-8692

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Skp2-mediated degradation of p27 regulates progression into Mitosis.2004

    • Author(s)
      Nakayama et al.
    • Journal Title

      Dev. Cell 6

      Pages: 661-672

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Molecular clearance of ataxin-3 is regulated by a mammalian E4.2004

    • Author(s)
      Matsumoto, M. et al.
    • Journal Title

      EMBO J 23

      Pages: 659-669

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Contribution of the constitutive and inducible degradation of Smad3 by the ubiquitin-proteasome pathway to transforming growth factor-β signaling.2004

    • Author(s)
      Inoue, Y. et al.
    • Journal Title

      J. Interferon & Cytokine Research, 24

      Pages: 43-54

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Cell cycle-dependent regulation of the human aurora B promoter.2004

    • Author(s)
      Kimura, M. et al.
    • Journal Title

      Biochem Biophys Res Commun. 361

      Pages: 930-936

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Treatment with anti-TGF-β antibody ameliorates progressive nephritis by inhibiting Smad/TGF-β signaling.2004

    • Author(s)
      Fukasawa, H. et al.
    • Journal Title

      Kidney Int. 65

      Pages: 63-74

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Expression of cytochrome P450 in tumor tissues and its association with cancer development.2004

    • Author(s)
      Oyama, T. et al.
    • Journal Title

      Front Biosci. 9

      Pages: 1967-1976

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Cellular FLIP inhibits β-catenin ubiquitylation and enhances Wnt signaling.2004

    • Author(s)
      Naito, M.
    • Journal Title

      Mol.Cell.Biol. 24

      Pages: 8418-8427

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Down-regulation of Smad7 expression by ubiquitin-dependent degradation contributes to renal fibrosis in mice obstructive nephropathy.2004

    • Author(s)
      Fukasawa, H.
    • Journal Title

      Proc.Nathl.Acad.Sci.USA 101(23)

      Pages: 8687-8692

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Skp2-mediated degradation of p27 regulates progression into Mitosis.2004

    • Author(s)
      Nakayama, K.
    • Journal Title

      Dev.Cell 6

      Pages: 661-672

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Molecular clearance of ataxin-3 is regulated by a mammalian E4.2004

    • Author(s)
      Matsumoto, M.
    • Journal Title

      EMBO J 23

      Pages: 659-669

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Contribution of the constitutive and inducible degradation of Smad3 by the ubiquitin-proteasome pathway to transforming growth factor-β signaling.2004

    • Author(s)
      Inoue, Y.
    • Journal Title

      J.Interferon & Cytokine Research 24

      Pages: 43-54

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Cell cycle-dependent regulation of the human aurora B promoter.2004

    • Author(s)
      Kimura, M.
    • Journal Title

      Biochem Biophys Res Commun. 316(3)

      Pages: 930-936

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Treatment with anti-TGF-β antibody ameliorates progressive nephritis by inhibiting Smad/TGF-β signaling.2004

    • Author(s)
      Fukasawa, H.
    • Journal Title

      Kidney Int. 65

      Pages: 63-74

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Expression of cytochrome P450 in tumor tissues and its association with cancer development.2004

    • Author(s)
      Oyama, T.
    • Journal Title

      Front Biosci. 9

      Pages: 1967-1976

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Cell cycle-dependent regulation of the human aurora B promoter.2004

    • Author(s)
      Masashi Kimura et al.
    • Journal Title

      Biochem Biophys Res Commun. 316

      Pages: 93-936

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Treatment with anti-TGF-β antibody ameliorates chronic progressive nephritis by inhibiting Smad/TGF-β signaling.2004

    • Author(s)
      Hirotaka Fukasawa et al.
    • Journal Title

      Kidney Int. 65・1

      Pages: 63-74

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Contribution of the constitutive and inducible degradation of Smad3 by the ubiquitin-proteasome pathway to transforming growth factor-β signaling.2004

    • Author(s)
      Yasumichi Inoue et al.
    • Journal Title

      J.Interferon & Cytokine Research 24

      Pages: 43-54

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Down regulation of Smad7 expression by ubiquitin-dependent degradation contributes to renal fibrosis in obstructive nephropathy in mice.2004

    • Author(s)
      Hirotaka Fukasawa et al.
    • Journal Title

      Proc Natl Acad Sci USA 101・23

      Pages: 8687-8692

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Molecular clearance of ataxin-3 is regulated by a mammalian E4.2004

    • Author(s)
      Masaki Matsumoto et al.
    • Journal Title

      EMBO J 23

      Pages: 659-669

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Skp2-mediated degradation of p27 regulates progression into Mitosis.2004

    • Author(s)
      Keiko Nakayama et al.
    • Journal Title

      Dev.Cell 6

      Pages: 661-672

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Cellular FLIP inhibits β-catenin ubiquitylation and enhances Wnt signaling2004

    • Author(s)
      Mikihiko Naito et al.
    • Journal Title

      Mol.Cell.Biol 24

      Pages: 8418-8427

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Expression of cytochrome P450 in tumor tissues and its association with cancer development.2004

    • Author(s)
      Tomohiro Oyama et al.
    • Journal Title

      Frontier in Bioscience 9

      Pages: 1967-1976

    • Related Report
      2004 Annual Research Report
  • [Book] キーワードで理解する細胞周期イラストマップ(中山敬一編)2005

    • Author(s)
      北川雅敏(分担執筆)
    • Total Pages
      190
    • Publisher
      羊土社
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Annual Research Report 2005 Final Research Report Summary
  • [Book] キーワードで理解する細胞周期イラストマップ(編集 中山敬一)2005

    • Author(s)
      北川雅敏
    • Total Pages
      189
    • Publisher
      羊土社
    • Related Report
      2004 Annual Research Report

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Published: 2004-04-01   Modified: 2016-04-21  

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