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発がんプロモ-ションの機構とその阻害

Research Project

Project/Area Number 02151077
Research Category

Grant-in-Aid for Cancer Research

Allocation TypeSingle-year Grants
Research InstitutionNational Cancer Center Research Institute and Research Center for Innovative Oncology, National Cancer Center Hospital East

Principal Investigator

藤木 博太  国立がんセンター研究所, がん予防研究部, 部長 (60124426)

Co-Investigator(Kenkyū-buntansha) 深見 泰夫  神戸大学, 遺伝子実験施設, 助教授 (00156746)
橋本 祐一  東京大学, 応用微生物研究所, 助教授 (90164798)
野瀬 清  東京大学, 医科学研究所・癌細胞, 助教授 (70012747)
大内 和雄  東北大学, 薬学部・病態生化学, 教授 (20006357)
石川 隆俊  東京大学, 医学部・病理, 教授 (30085633)
Project Period (FY) 1989 – 1991
Project Status Completed (Fiscal Year 1990)
Budget Amount *help
¥20,000,000 (Direct Cost: ¥20,000,000)
Fiscal Year 1990: ¥20,000,000 (Direct Cost: ¥20,000,000)
Keywordsオカダ酸 / オカダ酸クラス発がんプロモ-タ- / ミクロチスチン / 蛋白質脱リン酸化酵素2A / プロスタグランジンE_2 / protein kinase C / CNーTPBP
Research Abstract

新しい発がんプロモ-タ-、オカダ酸及びオカダ酸クラスの化合物を用いて、プロモ-ションの機構を解明している。オカダ酸クラスの発がんプロモ-タ-は、いづれも、そのレセプタ-である蛋白質脱リン酸化酵素1と2Aに結合し、その活性を抑制した。今回、光親和性オカダ酸誘導体, ^3Hーmethyl7ー0ー(4ーazidobenzoyl)okadaateを用い、精製した蛋白質脱リン酸化酵素2Aと反応させた。この精製した酵素は65kと42kの調節サブユニットと37kの触媒サブユニットからできている。反応液をSDSーPAGEで調べると、 ^3Hーアダクトは触媒サブユニットにのみ認められた。この結果から、オカダ酸は触媒サブユニットに結合し、その活性を抑制することが明らかになった。オカダ酸はNーmethylーN'ーnitroーNーnitroーsoguanidineでイニシエ-トしたラット腺胃に対し、微量で発がんプロモ-ション活性を示した。ミクロチスチンはdiethylnitrosamineでイニシエ-トしたラット肝に対し、微量で発がんプロモ-ション活性を示した。従って、脱リン酸化酵素の阻害を介するオカダ酸クラスの発がんプロモ-ション機構は、いろいろな臓器に共通することが証明された。NIHー3T3細胞と活性化したcーHー<ras>___ーをトランスフェクトしたF25ー15ー5細胞について、発がんプロモ-タ-によるプロスタグランジンE_2産生を比較検討すると,F25ー15ー5細胞の方が強く亢進していた。酵母に含まれる新しいタイプのprotein kinase Cを分離した。この酵素はジアシルグリセロ-ルの代わりに、ホルボ-ルエステルを加えても、活性化が認められなかった。TPAータイププロモ-タ-に特異的に結合する蛋白質(CNーTPBP)は細胞質でheat shock蛋白質90kDと複合体を形成する70kDの蛋白質であり、TPA処理により速やかに核へ移行することが見いだされた。3種のレチノイドレセプタ-は必ずしもmRNAレベルの分布と一致せず、それぞれ固有の役割を担うことが示唆された。

Report

(1 results)
  • 1990 Annual Research Report
  • Research Products

    (21 results)

All Other

All Publications (21 results)

  • [Publications] Suganuma,M.,Fujiki,H.,et al.: "Calyculin A,an inhibitor of protein phophatases,a potent tumor promoter on CDー1 mouse skin." Cancer Res.50. 3521-3525 (1990)

    • Related Report
      1990 Annual Research Report
  • [Publications] Nam,KーY.,Fujiki,H.,et al.: "Permeability of a nonーTPAーtype tumor promoter,okadaic acid,through lipid bilayer membrane." Carcinogenesis. 11. 1171-1174 (1990)

    • Related Report
      1990 Annual Research Report
  • [Publications] Yoshizawa,S.,Fujiki,H.,et al.: "Tumorーpromoting activity of staurosporine,a protein kinese inhibitor on mouse skin." Cancer Res.50. 4974-4978 (1990)

    • Related Report
      1990 Annual Research Report
  • [Publications] Nishiwaki,S.,Fujiki,H.,et al.: "Photoaffinity labeling of protein phosphatase 2A,the receptor for a tumor promoter okadaic acid,by(27ー^3H)methyl 7ーOー(4ーazidobenzoyl)okadaate." Biochem.Biophys.Res.Commun.170. 1359-1364 (1990)

    • Related Report
      1990 Annual Research Report
  • [Publications] Nishiwaki,S.,Fujiki,H.,et al.: "Stuructureーactivity relationship within a series of okadaic acid derivatives." Carcinogenesis. 11. 1837-1841 (1990)

    • Related Report
      1990 Annual Research Report
  • [Publications] Yoshizawa,S.,Fujiki,H.,et al.: "Inhibition of protein phophatases by microcystin and nodularin associated with hepatotoxicity." J.Cancer Res.Clin.Oncol.116. 609-614 (1990)

    • Related Report
      1990 Annual Research Report
  • [Publications] Hashimoto,Y.,et al.: "Cytosolicーnuclear tumor promoterーspecific binding protein (CNーTPBP) in human promyelocystic leukemia cells HLー60." Biochem.Biophys.Res.Commun.166. 1126-1132 (1990)

    • Related Report
      1990 Annual Research Report
  • [Publications] Hashimoto,Y.,et al.: "Expression of retinoic acid receptor genes and the ligandーbinding selectivity of retinoic acid receptors(RAR's)." Biochem.Biophys.Res.Commun.116. 1300-1307 (1990)

    • Related Report
      1990 Annual Research Report
  • [Publications] Sato,K.,Fukami,Y.,et al.: "A synthetic peptide corresponding to residues 137 to 157 of p60 Vーsrc inhibits tyrosineーspecific protein kinases." Biochem.Biophys.Res.Commun.171. 1152-1159 (1990)

    • Related Report
      1990 Annual Research Report
  • [Publications] Saitoh,A.,Izawa,M.,et al.: "Most tumors in transgenic mice with human cーHaー<ras>___ー gene contained somatically activated transgenes." Oncogene. 5. 1195-1200 (1990)

    • Related Report
      1990 Annual Research Report
  • [Publications] Hashida,T.,Yasumoto,S.: "Casein kinase II activities related to hyperーphosphoryーlation of human papillomavirus type 16ーE7 oncoーprotein in epidermal keratinocytes." Biochem.Biophys.Res.Commun.172. 958-964 (1990)

    • Related Report
      1990 Annual Research Report
  • [Publications] Nakadate,T.,Nishikawa,k.,et al.: "Hー7,a protein kinase C inhibitor,inhibits phorbol esterーcaused ornithine decarboxylase induction but fails to inhibit phorbol esterーcaused suppression of epidermal growth factor binding in primary cultured mouse epidermal cells." Mol.Pharmacol.36. 917-924 (1989)

    • Related Report
      1990 Annual Research Report
  • [Publications] Nemoto,N.,Ishikawa,T.,et al.: "Acquisition of aryl hydrocarbon hydroxylase inducibility by aromatic hydrocarbons in monolayerーcyltured hepatocytes from nonresponsive mouse strain." Cancer Res.50. 3226-3236 (1990)

    • Related Report
      1990 Annual Research Report
  • [Publications] Nakatsuru,Y.,Ishikawa,T.,et al.: "Immunological detection of <in>___ー <vivo>___ー aflatoxin B_1ーDNA adduct formation in rats,rainbow trout and coho salmon." Carcinogenesis. 11. 1523-1526 (1990)

    • Related Report
      1990 Annual Research Report
  • [Publications] Watanabe,M.,Fujiki,H.,Ohuchi,K.,et al.: "Dual effects of staurosporine on arachidonic acid metabolism in rat peritoneal macrophages." Biochem.Biophys.Acta. 1047. 141-147 (1990)

    • Related Report
      1990 Annual Research Report
  • [Publications] Nose,K.,et al.: "Abolishment of <cーfos>___ー inducibility in <ras>___ーーtranformed mouse osteoblastic cell lines." Mol.Carcinogenesis. 2. 208-216 (1990)

    • Related Report
      1990 Annual Research Report
  • [Publications] Nose,K.,et al.: "Isolation of a gene sequence induced later by tumor promoting 12ーOーtetradecanoylーphorbolー13ーacetate in mouse obteoblastic cells (MC3T3) and expressed constitutively in <ras>___ーーtransformed cells." Cell Growth & Defferentiation. 1. 511-518 (1990)

    • Related Report
      1990 Annual Research Report
  • [Publications] Hashimoto,Y.,et al.: "The retionic acid receptors α and β are expressed in the human promyelocytic leukemia cell line HLー60." Molecular Endocrinology. 3. 1046-1052 (1989)

    • Related Report
      1990 Annual Research Report
  • [Publications] Fujiki,H.,et al.: "New Tumor promoters from marine sources:The okadaic acid class.in “Mycotoxins and Phycotoxins '88"" Elsevier,Holland, 8 (1989)

    • Related Report
      1990 Annual Research Report
  • [Publications] Fujiki,H.,et al.: "A new pathway of tumor promotion by the okadaic acid class compounds.in “The Biology and Medicine of Singnal Transduction"" Raven Press, 5 (1990)

    • Related Report
      1990 Annual Research Report
  • [Publications] H.Fujiki,et al.: "A New Pathway of Tumor Promotion by the Okadaic acid class Compounds in Advances in Second Messenger and phosphoprotein Research" Y.Nishizuka,M.Endo,and C.Tanaka, 340-344 (1990)

    • Related Report
      1990 Annual Research Report

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Published: 1990-04-01   Modified: 2016-04-21  

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