1997 年度実績報告書

p53欠失マウスを用いた酸化的DNA損傷の関わる化学発がんプロモーター機序の解析

研究課題

研究課題/領域番号	09044353
研究機関	国立医薬品食品衛生研究所
研究代表者	井上達国立医薬品食品衛生研究所, 毒性部, 部長 (50100110)
研究分担者	佐井君江国立医薬食品衛生研究所, 毒性部, 研究員 (20195960) 長谷川隆一国立医薬品食品衛生研究所, 毒性部, 室長 (50112496) TROSKOJAMES ジェームス・イー・ミシガン州立大学, 小児科学・人類発生学部, 教授
キーワード	p53 / ペンタクロロフェノール / ギャップ結合細胞間コミュニケーション
研究概要	本研究は肝発がん性のpentachlorophenol(PCP)のプロモーター機序における酸化的DNA損傷、アポトーシス及び細胞間連絡(GJIC)阻害の相互関連性について、それらの制御に関わると考えられるp53欠失系で検討することを目的としている。これについて本年度は、日本側で(1)p53欠失マウスへのPCP投与試験を実施し、また日本からミシガン州立大学(Dr.Trosko研究室)へ研究員を派遣し、(2)培養細胞系でのPCPによるGJIC阻害作用に関する実験を実施した。またDr.Troskoを日本に招聘し、共同研究成果の報告及び今後の計画について打ち合わせ会議を行った。本年度の実績としては、(1)p53欠失マウスへのPCP投与試験では、p53野生型(p53+/+)及び欠失型(p53+/-,p53-/-)マウスにPCP(0〜300ppm)を2週間混餌投与し、肝の酸化的DNA損傷および細胞増殖作用を解析した。その結果、野生型マウスでのPCP投与量依存的な肝での酸化的DNA損傷ならびに細胞増殖作用に対して、p53欠失による増強性は認められず、この原因について現在検討中である。(2)培養肝細胞でのPCP及びその代謝産物TCHQによるGJIC)阻害作用に関する実験の結果、PCPにGJIC阻害作用が認められ、これにはコネクシンのリン酸化状態及び細胞膜状での発現とは関連性がないが、コネクシン発現量の低下との関連が認められた。一方、TCHQには阻害作用が見られなかった。このことから、PCPの直接的なGJIC阻害作用が発がんプロモーターに深く関与していることが示唆された。

研究成果
(15件)

すべてその他

すべて文献書誌 (15件)

[文献書誌] K.Sai, B.L.Upham, K.-S.Kang, R.Hasegawa, J.E.Trosko, T.Inoue: "Inhibitory effects of pentachlorophenol on gap junctional intercellular communication in rat liver epithelial cells in vitro." Cancer Letters.(in press). (1998)
[文献書誌] T.Inoue, Y.Hirabayashi, , H.Sasaki, M.Matsuda, Y.Furuta, S.Aizawa: "Model of Myelodysplastic Syndrome-like Myelodyaplasia that transforms into single lineage hemopoietic malignancies upon transplantation" International Journal of Pediatric Hematology/Oncology. 4. 221-230 (1997)
[文献書誌] J.E.Trosko and T.Inoue: "Oxidative stress,signal transduction,nd intercellular communication in radiation carcnogenesis." Stem Cell. 15. 59-70 (1997)
[文献書誌] K.S.-Kang, I.Morita, A.Cruz, Y.J.Jeon, J.E.Trosko, C.C.Chang: "Expression of estrogen receptors in a normal human breast epithelial cell type with luminal and stem cell characteristics and its neoplastically transformed cell lines." Carcinogenssis. 18. 251-257 (1997)
[文献書誌] H.Sasaki, M.Matsuda, Y.Lu, T.Inoue et al.: "A fraction unresponsive to growth inhibition by TGF-beta among the high-proliferafive potential progenitor cells in bone marrow of p53-deficient mice." Leukemia. 11. 239-244 (1997)
[文献書誌] Y.Hiyabayashi, M.Matsuda, T.Matsuda, T.Inoue et al.: "The p53-deficient hemopoietic stem cells:resistance to radiation-apoptosis,but lasted transiently." Leukemia. 11 Suppl.489-492 (1997)
[文献書誌] M.Mishimura-Morita, M.Nose, T.Inoue et al.: "Amelioration of systemic autoimmune disease by the stimulation of apoptpsis-promoting receptor Fas with anti-Fas mAb." International Immunology. 9. 307-316 (1997)
[文献書誌] T.Inoue, E.P.Cronkite, Y.Hirabayashi, et al.: "Lifetime treatment of mice with azidothymidine(AZT)produces myelodysplasia." Leukemia. 11 Suppl.123-127 (1997)
[文献書誌] K.Yoshida, T..Inoue, K.Nojima, et al.: "Calorie restriction reduces the incidence of myeloid leukemia induced by a single whole-body radiation in C3H/He mice." Proc.Natil.Acad.Sci.USA. 94. 2615-2619 (1997)
[文献書誌] K.Yoshida, T.Inoue, Y.Hiyabayashi, et al: "Radiation-inducedmyeloid leukemia in mice under caloric restriction." Leukeimia. 11 Suppl. 410-412 (1997)
[文献書誌] T.Hayashi, D.F.Matesic, K.S.Kang, J.E.Trosko: "Stimulation of cell proliferation and inhibition of gap junctional intercellular communication by linoleic acid." Cancer Letters. 112. 103-111 (1997)
[文献書誌] B.L.Upham, K, S, Kang, H.Y.Cho, J.E.Trosko: "Hydrogen peroxide inhibits gap junctional intercellular communication via hyper-phosphorylation of connexin 43in glutathione sufficient but not glutathione deficient cells" Carcinogenesis. 18. 37-42 (1997)
[文献書誌] J.E.Trosko: "Challenge to the simple paradigm that ‘carcinogens' are ‘mutagens' and to the in vitro and in vivo assays used to test the paradigm." Mutation Research. 3. 245-249 (1997)
[文献書誌] K.S.Kang, C.C.Chang, J.E.Trosko: "Modulation of gap junctional intercellular communication during human breast stem cell differentiation and immortalization.In Gap Junctions" IOS press,R.Werner(ed.), 358(347-351) (1998)
[文献書誌] M.R.Wilson, U.Ifeanyi, K.S-Kang, J.E.Trosko: "A role for mitogen activated protein kinase(MAKP)during ras-induced down regulation of gap junctional intercellular communication In:Gap Junctions" IOS press,R.Werner(ed.), 385(239-243) (1998)

1997 年度 実績報告書

p53欠失マウスを用いた酸化的DNA損傷の関わる化学発がんプロモーター機序の解析

研究代表者

井上 達 国立医薬品食品衛生研究所, 毒性部, 部長 (50100110)

研究成果

[文献書誌] K.Sai, B.L.Upham, K.-S.Kang, R.Hasegawa, J.E.Trosko, T.Inoue: "Inhibitory effects of pentachlorophenol on gap junctional intercellular communication in rat liver epithelial cells in vitro." Cancer Letters.(in press). (1998)

[文献書誌] T.Inoue, Y.Hirabayashi, , H.Sasaki, M.Matsuda, Y.Furuta, S.Aizawa: "Model of Myelodysplastic Syndrome-like Myelodyaplasia that transforms into single lineage hemopoietic malignancies upon transplantation" International Journal of Pediatric Hematology/Oncology. 4. 221-230 (1997)

[文献書誌] J.E.Trosko and T.Inoue: "Oxidative stress,signal transduction,nd intercellular communication in radiation carcnogenesis." Stem Cell. 15. 59-70 (1997)

[文献書誌] K.S.-Kang, I.Morita, A.Cruz, Y.J.Jeon, J.E.Trosko, C.C.Chang: "Expression of estrogen receptors in a normal human breast epithelial cell type with luminal and stem cell characteristics and its neoplastically transformed cell lines." Carcinogenssis. 18. 251-257 (1997)

[文献書誌] H.Sasaki, M.Matsuda, Y.Lu, T.Inoue et al.: "A fraction unresponsive to growth inhibition by TGF-beta among the high-proliferafive potential progenitor cells in bone marrow of p53-deficient mice." Leukemia. 11. 239-244 (1997)

[文献書誌] Y.Hiyabayashi, M.Matsuda, T.Matsuda, T.Inoue et al.: "The p53-deficient hemopoietic stem cells:resistance to radiation-apoptosis,but lasted transiently." Leukemia. 11 Suppl.489-492 (1997)

[文献書誌] M.Mishimura-Morita, M.Nose, T.Inoue et al.: "Amelioration of systemic autoimmune disease by the stimulation of apoptpsis-promoting receptor Fas with anti-Fas mAb." International Immunology. 9. 307-316 (1997)

[文献書誌] T.Inoue, E.P.Cronkite, Y.Hirabayashi, et al.: "Lifetime treatment of mice with azidothymidine(AZT)produces myelodysplasia." Leukemia. 11 Suppl.123-127 (1997)

[文献書誌] K.Yoshida, T..Inoue, K.Nojima, et al.: "Calorie restriction reduces the incidence of myeloid leukemia induced by a single whole-body radiation in C3H/He mice." Proc.Natil.Acad.Sci.USA. 94. 2615-2619 (1997)

[文献書誌] K.Yoshida, T.Inoue, Y.Hiyabayashi, et al: "Radiation-inducedmyeloid leukemia in mice under caloric restriction." Leukeimia. 11 Suppl. 410-412 (1997)

[文献書誌] T.Hayashi, D.F.Matesic, K.S.Kang, J.E.Trosko: "Stimulation of cell proliferation and inhibition of gap junctional intercellular communication by linoleic acid." Cancer Letters. 112. 103-111 (1997)

[文献書誌] B.L.Upham, K, S, Kang, H.Y.Cho, J.E.Trosko: "Hydrogen peroxide inhibits gap junctional intercellular communication via hyper-phosphorylation of connexin 43in glutathione sufficient but not glutathione deficient cells" Carcinogenesis. 18. 37-42 (1997)

[文献書誌] J.E.Trosko: "Challenge to the simple paradigm that ‘carcinogens' are ‘mutagens' and to the in vitro and in vivo assays used to test the paradigm." Mutation Research. 3. 245-249 (1997)

[文献書誌] K.S.Kang, C.C.Chang, J.E.Trosko: "Modulation of gap junctional intercellular communication during human breast stem cell differentiation and immortalization.In Gap Junctions" IOS press,R.Werner(ed.), 358(347-351) (1998)

[文献書誌] M.R.Wilson, U.Ifeanyi, K.S-Kang, J.E.Trosko: "A role for mitogen activated protein kinase(MAKP)during ras-induced down regulation of gap junctional intercellular communication In:Gap Junctions" IOS press,R.Werner(ed.), 385(239-243) (1998)

1997 年度実績報告書

井上達国立医薬品食品衛生研究所, 毒性部, 部長 (50100110)