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インスリン産生細胞増殖因子RegのCDK阻害系による細胞周期調節

Research Project

Project/Area Number 16026203
Research Category

Grant-in-Aid for Scientific Research on Priority Areas

Allocation TypeSingle-year Grants
Review Section Biological Sciences
Research InstitutionTohoku University

Principal Investigator

高沢 伸  東北大学, 大学院・医学系研究科, 助教授 (50187944)

Co-Investigator(Kenkyū-buntansha) 岡本 宏  東北大学, 大学院・医学系研究科, 教授 (60025632)
Project Period (FY) 2004 – 2005
Project Status Completed (Fiscal Year 2005)
Budget Amount *help
¥3,700,000 (Direct Cost: ¥3,700,000)
Fiscal Year 2005: ¥1,900,000 (Direct Cost: ¥1,900,000)
Fiscal Year 2004: ¥1,800,000 (Direct Cost: ¥1,800,000)
Keywords遺伝子 / 再生医学 / 糖尿病 / 発現制御 / Reg蛋白質 / Reg遺伝子 / インスリン産生細胞 / 心筋 / CDK4 / p19^<INK4D> / 細胞周期調節 / 再生増殖
Research Abstract

本研究の目的は、インスリン産生細胞増殖因子として見出されたReg蛋白質による細胞周期調節機構を明らかにすることである。
1.インスリン産生細胞由来の培養細胞(RINm5F細胞)、Reg遺伝子ノックアウトマウスを用いた実験から、Reg蛋白質による細胞周期調節はCDKの抑制解除よりはCDKの活性化が中心であり、その機構は「Reg蛋白質→Reg蛋白質受容体→PI3キナーゼの活性化→PI3キナーゼによるATF2のリン酸化→リン酸化ATF2のサイクリンD1プロモーターへの結合→サイクリンD1の転写活性化→サイクリンD1量の増加→CDK4の活性化→細胞周期G1からSへの進行」であることが明らかになった(Takasawa et al. FEBS Lett. 580,585-591,2006)。
2.また、新規にReg蛋白質以外にインスリン産生細胞に対する増殖因子として機能する可能性を持つIGF(Insulin-like growth factor)-Iを膵臓組織特異的ノックアウトしたマウスを作製したところ、このマウスでは、代償的にReg遺伝子の発現が上昇し、その結果、Reg蛋白質-Reg受容体系を介して膵β細胞の再生増殖が起こることが明らかになった(Lu et al. Am.J.Physiol.Endocrionl.Metab.in press)。
3.またさらに、本研究で明らかにしてきたReg蛋白質による細胞周期の調節(活性化)がインスリン産生細胞のみならず、組織損傷を受けた後の心筋細胞(Kiji et al. Am.J.Physiol.Heart Circ.Physiol.289,H277-H284,2005)や神経細胞(Namikawa et al.Biochem.Biophys.Res.Commun.322,126-134,2005)の再生においても機能していることも明らかになった。

Report

(2 results)
  • 2005 Annual Research Report
  • 2004 Annual Research Report
  • Research Products

    (55 results)

All 2006 2005 2004

All Journal Article (55 results)

  • [Journal Article] Cyclin D1 activation through ATF-2 in Reg-induced pancreatic β-cell regeneration.2006

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

      FEBS Lett. 580

      Pages: 585-591

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Activation of the Reg family genes by pancreatic-specific IGF-I gene deficiency and after streptozotocin-induced diabetes in mouse pancreas.2006

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

      Am.J.Physiol.Endocrinol.Metab. (In press)

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Identification of mouse ortholog of endogenous secretory receptor for advanced glycation endproducts : structure, function and expression.2006

    • Author(s)
      Harashima, A.
    • Journal Title

      Biochem.J. (In press)

    • Related Report
      2005 Annual Research Report
  • [Journal Article] A severe diabetic nephropathy model with early development of nodule-like lesions induced by megsin overexpression in RAGE/INOS transgenic mice.2006

    • Author(s)
      Inagi, R.
    • Journal Title

      Diabetes 55

      Pages: 356-366

    • Related Report
      2005 Annual Research Report
  • [Journal Article] 胎児期マウス肝臓ではinsulinが発現している2006

    • Author(s)
      高沢 伸
    • Journal Title

      糖尿病 49(in press)

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Interleukin-8 regulates expression of Reg protein in Helicobacter pylori-infected gastric mucosa.2005

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

      Am.J.Gastroenterol. 100

      Pages: 2157-2166

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Genomic organization, chromosomal localization, and promoter of human gene for FK506-binding protein 12.6.2005

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

      Gene 360

      Pages: 55-64

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Receptor for advanced glycation end products is a promising target of diabetic nephropathy.2005

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

      Ann.NY Acad.Sci. 1043

      Pages: 562-566

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Activation of regenerating gene in rat and human hearts in response to acute stress.2005

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

      Am.J.Physiol.Heart Circ.Physiol. 289

    • Related Report
      2005 Annual Research Report
  • [Journal Article] A novel ryanodine receptor expressed in pancreatic islets and its possible role in the cyclic ADP-ribose-induced intracellular calcium mobilization.2005

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

      Diabetologia 48

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Identification of islet-type ryanodine receptor and its cyclic ADP-ribose-induced intracellular Ca^<2+> mobilization.2005

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

      Diabetes 54

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Molecular cloning, expression and chromosomal localization of a novel human REG family gene, REG III.2005

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

      Diabetes 54

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Pancreatic beta-cell regeneration by Regenerating gene (Reg) and a possible therapeutic use of Reg gene and/or Reg protein in diabetes treatment.2005

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

      Int.J.Artificial Organs 28

      Pages: 329-330

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Expression of Reg/PAP family members during motor nerve regeneration in rat.2005

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

      Biochem.Biophys.Res.Commun. 332

      Pages: 126-134

    • Related Report
      2005 Annual Research Report
  • [Journal Article] REG Iα protein may function as a trophic and/or anti-apoptotic factor in the development of gastric cancer.2005

    • Author(s)
      Sekikawa, A.
    • Journal Title

      Gastroenterology 128

      Pages: 642-653

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Anti-CD38 autoimmunity in children with newly diagnosed type 1 diabetes mellitus.2005

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

      J.Pediatr.Endocrinol.Metab. 18

      Pages: 1417-1423

    • Related Report
      2005 Annual Research Report
  • [Journal Article] チアゾリジン誘導体によるREG(Regenerating gene)遺伝子の発現抑制2005

    • Author(s)
      高橋 巌
    • Journal Title

      糖尿病 48

    • Related Report
      2005 Annual Research Report
  • [Journal Article] ラ島型リアノジン受容体の発見とそのサイクリックADPリボース感受性2005

    • Author(s)
      高沢 伸
    • Journal Title

      糖尿病 48

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Mutant Cam Kinase2遺伝子導入による1型糖尿病および糖尿病性腎症モデルマウスの新規開発2005

    • Author(s)
      加藤一郎
    • Journal Title

      糖尿病 48

    • Related Report
      2005 Annual Research Report
  • [Journal Article] 新規ヒトREGファミリー遺伝子(REGIII)の単離:ヒトREGファミリーは5つの遺伝子によって構成されている2005

    • Author(s)
      那谷耕司
    • Journal Title

      糖尿病 48

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Genomic organization, chromosomal localization, and promoter of human genes for FK506-binding protein (FKBP) 12.6 and FKBP12.2005

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

      生化学 77

      Pages: 930-930

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Embryonic lethality caused by targeted disruption of the mouse Reg protein receptor gene.2005

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

      生化学 77

      Pages: 1031-1031

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Inhibition by thiazolidinediones of REG gene expression and proliferation in gastrointestinal cancer cells.2005

    • Author(s)
      Yamauchi, A.
    • Journal Title

      生化学 77

      Pages: 1036-1036

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Systemic analyses of retinas of transgenic mice overexpressing constitutively active form of CaM kinase II.2005

    • Author(s)
      Ichsan, A.M.
    • Journal Title

      生化学 77

      Pages: 1069-1069

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Expression of constitutively active form of CaM kinase II in pancreatic beta cells of transgenic mice leads to severe diabetes mellitus.2005

    • Author(s)
      Kato, I.
    • Journal Title

      生化学 77

      Pages: 1069-1069

    • Related Report
      2005 Annual Research Report
  • [Journal Article] チアゾリジン誘導体によるREG(Regenerating gene)遺伝子の発現抑制とがん細胞の増殖抑制2005

    • Author(s)
      高沢 伸
    • Journal Title

      第64回日本癌学会学術総会記事

      Pages: 312-312

    • Related Report
      2005 Annual Research Report
  • [Journal Article] 糖尿病治療薬(チアゾリジン誘導体)による消化管がん細胞のREG遺伝子発現抑制と増殖抑制2005

    • Author(s)
      高沢 伸
    • Journal Title

      糖尿病合併症 19

      Pages: 48-48

    • Related Report
      2005 Annual Research Report
  • [Journal Article] 膵β細胞の再生2005

    • Author(s)
      高沢 伸
    • Journal Title

      第40回糖尿病学の進歩・プログラム・講演要旨

      Pages: 90-90

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Activation of Regenerating gene (Reg) in rat and human hearts in response to myocardial infarction.2005

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

      Circulation Journal 69

      Pages: 582-582

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Two store-operated Ca^<2+> influxes with differential sensitivities to Zn^<2+> in mouse salivary gland acinar cells.2005

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

      Jpn.J.Physiol. 55

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Activation of regenerating gene (Reg) in rat and human hearts in response to acute stress.2005

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

      Am.J.Physiol. (In press)

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Mutant CaM Kinase2遺伝子導入による1型糖尿病および糖尿病性腎症モデルマウスの新規開発2005

    • Author(s)
      加藤一郎
    • Journal Title

      糖尿病 48(In press)

    • Related Report
      2004 Annual Research Report
  • [Journal Article] ラ島型リアノジン受容体の発見とそのサイクリックADPリボース感受性2005

    • Author(s)
      高沢 伸
    • Journal Title

      糖尿病 48(In press)

    • Related Report
      2004 Annual Research Report
  • [Journal Article] チアゾリジン誘導体によるREG (Regenerating gene)遺伝子の発現抑制2005

    • Author(s)
      高橋 巌
    • Journal Title

      糖尿病 48(In press)

    • Related Report
      2004 Annual Research Report
  • [Journal Article] 新規ヒトREGファミリー(REG III)の単離:ヒトREGファミリーは5つの遺伝子によって構成されている2005

    • Author(s)
      那谷耕司
    • Journal Title

      糖尿病 48(In press)

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Expression of Regenerating gene I in gastric adenocarcinomas : Correlation with tumor differentiation status and patient survival.2004

    • Author(s)
      Dhar, D.A.
    • Journal Title

      Cancer 100

      Pages: 1130-1136

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Molecular cloning, expression and chromosomal localization of a novel human REG family gene, REG III2004

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

      Gene 340

      Pages: 161-170

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Transgenic overexpression of Reg protein caused gastric cell proliferation and differentiation along parietal cell and chief cell lineages.2004

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

      Oncogene 23

      Pages: 3572-3579

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Autoantibodies to REG, a beta-cell regeneration factor, in diabetic patients.2004

    • Author(s)
      Shervani, N.J.
    • Journal Title

      Eur.J.Clin.Invest. 34

      Pages: 752-758

    • Related Report
      2004 Annual Research Report
  • [Journal Article] REG I as a marker for human pancreatic acinoductal cells.2004

    • Author(s)
      Tezel, E.
    • Journal Title

      Hepatogastroenterology 51

      Pages: 91-96

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Cyclin D1 activation through ATF-2 in Reg-induced pancreatic beta-cell regeneration.2004

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

      Diabetes 53

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Cyclic ADP-ribose, a putative Ca^<2+> mobilizing second messenger, operates in submucosal gland acinar cells.2004

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

      Am.J.Physiol. 287

    • Related Report
      2004 Annual Research Report
  • [Journal Article] 膵β細胞死と再生2004

    • Author(s)
      高沢 伸
    • Journal Title

      糖尿病カレントライブラリー 2

      Pages: 59-63

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Reg蛋白質による細胞周期活性化機構2004

    • Author(s)
      高沢 伸
    • Journal Title

      糖尿病 47

    • Related Report
      2004 Annual Research Report
  • [Journal Article] 糖尿病腎症におけるRAGEの役割-RAGEノックアウトマウス(RAGE^<-1->)を用いて-2004

    • Author(s)
      山本靖彦
    • Journal Title

      糖尿病 47

    • Related Report
      2004 Annual Research Report
  • [Journal Article] マウス胎児肝におけるインスリン遺伝子IとIIの発現2004

    • Author(s)
      川口晶子
    • Journal Title

      糖尿病 47

    • Related Report
      2004 Annual Research Report
  • [Journal Article] A novel ryanodine receptor and its possible roles in cyclic ADP-ribose-induced Ca^<2+> mobilization.2004

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

      生化学 76

      Pages: 916-916

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Molecular cloning and characterization of Xenopus cyclic ADP-ribose synthesizing enzyme, CD38.2004

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

      生化学 76

      Pages: 918-918

    • Related Report
      2004 Annual Research Report
  • [Journal Article] REG (Regenerating gene) expression in human colon and gastric cancer cells.2004

    • Author(s)
      Yamauchi, A.
    • Journal Title

      生化学 76

      Pages: 1098-1098

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Low molecular weight heparin-a potential RAGE inhibitor against diabetic nephropathy.2004

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

      生化学 76

      Pages: 1113-1113

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Pancreatic β-cell regeneration by Reg gene and Reg protein.2004

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

      膵臓 19

      Pages: 231-231

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Reg1 gene expression in gastric cancer.2004

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

      Cancer Science 95(Suppl.)

      Pages: 329-329

    • Related Report
      2004 Annual Research Report
  • [Journal Article] REG gene expression in colon and gastric cancer cells.2004

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

      Cancer Science 95(Suppl.)

      Pages: 429-429

    • Related Report
      2004 Annual Research Report
  • [Journal Article] 両棲類CD38の構造と機能:CD38-cADPR情報伝達系の進化における保存性2004

    • Author(s)
      池田崇之
    • Journal Title

      生化学 76

      Pages: 1235-1235

    • Related Report
      2004 Annual Research Report
  • [Journal Article] マウス胎児肝におけるインスリン遺伝子IとIIの発現2004

    • Author(s)
      川口晶子
    • Journal Title

      Diabetes Frontier 15

      Pages: 566-567

    • Related Report
      2004 Annual Research Report

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Published: 2004-04-01   Modified: 2018-03-28  

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