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p53標的遺伝子群の転写活性化を指標にした消化器癌の抗癌剤感受性の検索

Research Project

Project/Area Number 13877030
Research Category

Grant-in-Aid for Exploratory Research

Allocation TypeSingle-year Grants
Research Field Human pathology
Research InstitutionDokkyo Medical University

Principal Investigator

藤盛 孝博  獨協医科大学, 医学部, 教授 (30095385)

Co-Investigator(Kenkyū-buntansha) 川又 均  獨協医科大学, 医学部, 助教授 (70224847)
Project Period (FY) 2001 – 2002
Project Status Completed (Fiscal Year 2002)
Budget Amount *help
¥2,000,000 (Direct Cost: ¥2,000,000)
Fiscal Year 2002: ¥600,000 (Direct Cost: ¥600,000)
Fiscal Year 2001: ¥1,400,000 (Direct Cost: ¥1,400,000)
Keywords消化器癌 / p53 / p53標的遺伝子 / GFP / アポトーシス / 細胞周期 / p21waf1 / BAX / MDM2 / 抗癌剤 / 転写調整 / ルシフェラーゼアッセイ
Research Abstract

種々の消化器癌に存在するp53遺伝子の機能的な異常を検索するシステムの開発を試みた。まず,種々の消化器癌培養細胞(HSG,TYS,BHY,HNt,AZA1,AZA3)よりp53 cDNAの全翻訳領域をPCRで増幅し,蛍光蛋白質GFP遺伝子を有する発現ベクターに組み込んだ。全塩基配列を決定すると同時に,細胞内局在,標的遺伝子(p21waf1,MDM2,BAX,p53AIP1,PUMA)に対する転写活性化能を検索した。ヒト骨肉腫細胞であるSaos-2細胞に癌細胞由来のp53遺伝子を発現させたところ,AZA1,AZA3由来の野生型p53とHSG由来の変異p53(Asn30Ser),TYS由来の変異p53(ASP30His)は明らかに核に局在した。びまん性に細胞質に拡散が認められた。また,HSG由来p53は野生型とほぼ同様の転写活性化能を有し,HNt由来p53(Glu17Lys,His193Leu), BHY由来p53(delta121)は全く転写活性化能を示さなかった。TYS由来p53はMDM2,BAX,p53AIP1,PUMAに対しては転写活性化能を示さないが,p21waf1に対してはむしろ野生型よりも強い転写活性化能を有していた。このようなp53変異はDNA障害に際し,細胞周期は止めるが,アポトーシスは誘導しないという,癌細胞の生存あるいは悪性形質獲得に極めて重要な変異であると考えられる。同様の方法で進行大腸癌組織において同様の検索を行ったところ,免疫染色で全くp53蛋白質が染色されないが,PCR-SSCPではExon 5とExon 8にmobility shiftが見られる症例で,従来の方法では検索しないExon 4に大きな約100bpの塩基欠失が見られ,その結果フレームシフトによりトランケート型のp53蛋白を産生するような変異を検出した。以上の結果から,我々が構築したp53機能異常検索システムは多様なp53の機能異常を検索することが可能であると考える。

Report

(2 results)
  • 2002 Annual Research Report
  • 2001 Annual Research Report
  • Research Products

    (14 results)

All Other

All Publications (14 results)

  • [Publications] 品川 泰弘(他6名): "p53機能解析からみた頭頸部癌の抗癌剤感受性の検索"頭頸部腫瘍. 28. 264-268 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Y Shinagawa et al.: "Evaluation of the chemosensitivity of head and neck cancer cells based on the diverse function of mutated-p53"International Journal of Oncology. 22. 383-389 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Fujimori T, Kawamata H, Ichikawa K, Ono Y, Okura Y, Tomita S, Imura J.: "Pathological issues of gastric and lower esophageal cancer ; Helicobacter pylori infection and its eradication"Journal of Gastroenterology. (in press). (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Tomita S, Kawamata H, Imura J, Omotehara F, Ueda Y, Fujimori T.: "Frequent polym or orphim of PPARγ(Peroxisome Proliferator Activated Receptor γ)gene in colorectal cancer containing wild type K-ras gene"International Journal of Molecular Medicine. (in press). (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Fujii S, Fujimori T, Kashida H.: "UC-associated neoplasia"Pathology International. (in press). (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Furihata T, Kawamata H, Kubota K, Fujimori T.: "Evaluation of the Malignant Potential of Aberrant Crypt Foci by Immunohistochemical Staining for β -catenin in Inflammation-Induced Rat Colon Carcinogenesis"International Journal of Molecular Medicine. (in press). (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Ichikawa K, Imura J, Kawamata H, Takeda J, Fujimori T.: "Down-regulated p16 Expression Predicts Poor Prognosis in Patients with Extrahepatic Biliary Tract Carcinomas"International Journal of Oncology. 20(3). 453-461 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Kaihara T, Kusaka T, Kawamata H, Oda Y, Fujii S, Morita K, Imura J, Fujimori T.: "Decreased Expression of E-cadherin and Yamamoto-Kohama's Mode of Invasion highly Correlates with Lymph Node Metastasis in Esophageal Squamous Cell Carcinoma"Pathobiology. 69(3). 172-178 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Hino S, Kawamata H, et al.: "TSC-22(transforming growth factor--stimulated clone-22)enhances the radiation-sensitivity of salivary gland cancer cells"Biochemical and Biophysical Research Communications. (in press). (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Hino S, Kawamata H, et al.: "Leucine zipper structure of TSC-22(TGF-beta stimulated clone-22)markedly inhibits the anchorage-independent growth of salivary gland cancer cells"Oncology Report. 9(2). 371-374 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] M.O.Hoque, Kawamata H, et al.: "Dihydropyrimidne dehydrogenase mRNA level correlates with the response to 5-Fluorouracil-based chemo-immuno-radiation therapy in human oral squamous cell cancer."International Journal of Oncology. 19(5). 953-958 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Uchida D, Kawamata H, et al.: "Low-dose retinoic acid enhances in vitro invasiveness of human oral sqnamous-cell-carcinoma cell lines"British Journal of Cancer. 85(1). 122-128 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Uchida D, Kawamata H, et al.: "Role of HGF/c-met system in invasion and metastasis of oral squamous cell carcinoma cells in vitro and its clinical significance"International Journal of Cancer. 93(4). 489-496 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Furihata T, Sakai T, Kawamata H, et al.: "A new in vivo model for studying invasion and metastasis of esophageal squamous cell carcinoma"International Journal of Oncology. 19(5). 903-907 (2001)

    • Related Report
      2001 Annual Research Report

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Published: 2001-04-01   Modified: 2016-04-21  

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