2000 Fiscal Year Annual Research Report

ジーンターゲティングによるがん関連遺伝子の機能解析

Research Project

Project/Area Number	12213009
Research Category	Grant-in-Aid for Scientific Research on Priority Areas (C)
Research Institution	Tohoku University
Principal Investigator	野田哲生東北大学, 大学院・医学系研究科, 教授 (10183550)
Co-Investigator(Kenkyū-buntansha)	上條岳彦信州大学, 医学部, 助手 (90262708) 鈴木聡大阪大学, 微生物病研究所, 講師 (10311565) 高野洋志東北大学, 大学院・医学系研究科, 助手 (00241555)
Keywords	ジーンターゲティング / 癌抑制遺伝子 / SMAD4遺伝子 / VHL遺伝子 / ARF遺伝子 / PTEN遺伝子 / ノックアウトマウス / p53遺伝子
Research Abstract	ヒトの発癌は、がん遺伝子やがん抑制遺伝子といったがん関連遺伝子の変異により生じることが明らかとなっているが、その発癌の分子機構を解明するには、発癌の母地となる組織・細胞における、これらがん関連遺伝子の機能を知ることが重要である。本研究では、実際に高頻度にヒト癌においてその変異が検出されるSMAD4、VHL、PTEN、ARF等の遺伝子に対し、コンディショナル・ジーン・ターゲティングを応用し、これらの遺伝子の機能解析を行い、以下の結果を得た。 (1)膵臓特異的なSMAD4遺伝子の不活化を行ったが、細胞増殖の誘導は観察されず、また、長期観察においても腫瘍の発生は認められなかった。これらの結果から膵臓上皮細胞の癌化にはSMAD4遺伝子の不活化のみでは充分でないことが明らかとなった。 (2)VHL遺伝子変異のホモ接合体である変異ES細胞の解析から、VHL遺伝子はアドレノメデュリン遺伝子の発現を負に抑制していることが明らかとなり、さらにこの制御にはHIF2α遺伝子が関与していると考えられた。 (3)T細胞特異的なジーンターゲティングにより、PTEN遺伝子がCD4陽性のT細胞の増殖を負に制御し、アポトーシスの誘導に機能していることが示され、さらにこれらの機能が実際に生体内でリンパ腫発生の抑制に働いていることが明らかとなった。 (4)ノックアウトマウス由来の線維芽細胞の解析から、ARFを介したアポトーシス誘導機構には、p53依存性及び非依存性の2種類が存在すること、そしてそのいずれもがミトコンドリア依存性のアポトーシスであることが明らかとなった。

Research Products

(20 results)

All Other

All Publications (20 results)

[Publications] Noda,T., et: "A defect in a signal allele of the Mlh1 gene causes dissociation of the killing and tumorigenic actions of an alkylating carcinogen in methyltransferase-deficient mice."Carcinogenesis. 21(2). 301-305 (2000)
[Publications] Noda,T., et: "Targeted disruption of the homeobox transcription factor Bapx1 results in lethal skeletal dysplasia with asplenia and gastroduodenal malformation."Genes to Cells. 5. 499-513 (2000)
[Publications] Noda,T., et: "A role for hematopoietic stem cells in promoting angiogenesis."Cell. 102. 199-209 (2000)
[Publications] Noda,T., et: "BMP Type2 receptor is required for gastrulation and early development of mouse embryos."Dev.Biol.. 221(1). 249-258 (2000)
[Publications] Noda,T., et: "Altered pain responses in mice lacking alpha 1E subunit of the voltage-dependent Ca2+ channel."Proc.Natl.Acad.Sci.USA. 97(11). 6132-6137 (2000)
[Publications] Noda,T., et: "Distribution of Nociceptin/orphanin FQ precursor ptotein and receptor in brain and spinal cord : a study using in situ hybridization and X-gal histochemistry in receptor-deficient mice."J.Comp.Neurol.. 424. 489-508 (2000)
[Publications] Noda,T., et: "Rescue of embryonic lethality in hepatocyte growth factor/scatter factor knockout mice."Genesis. 27. 99-103 (2000)
[Publications] Noda,T., et: "Negative regulation of BMP/Smad signaling by Tobin osteoblasts."Cell. 103. 1085-1097 (2000)
[Publications] Noda,T., et: "Complex phenotype of mice lacking occuldin, a component of tight junction strands."Mol.Biol.Cell. 11. 4131-4142 (2000)
[Publications] Noda,T., et: "Requirement of Runx1/AML1/PEBP2 α B for the generation of hematopoietic cells from endothelial cells."Genes to Cells. (in press). (2000)
[Publications] Noda,T., et: "ASK1 is required for sustained activations of JNK/p38 MAP kinase and apoptosis."EMBO Rep.. (in press). (2000)
[Publications] Takano,H., et: "Impairment of antigen-presenting cell function in mice lacking expression of OX40 ligand."J.Exp.Med.. 191(2). 365-374 (2000)
[Publications] Takano,H., et: "Mmh/Ogg1 gene inactivation results in accumulation of 8-hydroxyguanine in mice."Proc.Natl.Acad.Sci.USA. 87(8). 4156-4161 (2000)
[Publications] Suzuki,A., et: "Colorectal carcinomas in mice lacking the catalytic subunit of PI(3)K gammma."Nature. 406. 897-902 (2000)
[Publications] Suzuki,A., et: "High incidence of breast and endometrial neoplasia resembling human Cowden syndrome in pten+/- mice."Cancer Res.. 60. 3605-3611 (2000)
[Publications] Suzuki,A., et: "Function of PI3K gamma in thymocyte development, T cell activation, and neutrophilmigration."Science. 287. 1040-1046 (2000)
[Publications] Kamijo,T., et: "An increase in circulating mast cell colony-forming cells in asthma."J.Immunol.. (in press). (2000)
[Publications] Kamijo,T., et: "A Novel missense mutation (Tyr88 to Cys) in the platlet membrane : glycoprotein 1bbeta gene affects the expression of GP1b/1X complex."Thrombosis and Haenostasis. (in press). (2000)
[Publications] Kamijo,T., et: "Related Articles Thrombopoietin enhances neutrophil production by bone marrow hematopoietic progenitors with the aid of stem cell factor in congenital neutropenia."J.Leukoc.Biol.. 68. 137-143 (2000)
[Publications] Kamijo,T., et: "Related Articles Retinoic acid is a negative regulator for the differentiation of cord blood-derived human mast cell progenitors."Blood. 95. 2821-2828 (2000)

2000 Fiscal Year Annual Research Report

ジーンターゲティングによるがん関連遺伝子の機能解析

Principal Investigator

野田 哲生 東北大学, 大学院・医学系研究科, 教授 (10183550)

Research Products

[Publications] Noda,T., et: "A defect in a signal allele of the Mlh1 gene causes dissociation of the killing and tumorigenic actions of an alkylating carcinogen in methyltransferase-deficient mice."Carcinogenesis. 21(2). 301-305 (2000)

[Publications] Noda,T., et: "Targeted disruption of the homeobox transcription factor Bapx1 results in lethal skeletal dysplasia with asplenia and gastroduodenal malformation."Genes to Cells. 5. 499-513 (2000)

[Publications] Noda,T., et: "A role for hematopoietic stem cells in promoting angiogenesis."Cell. 102. 199-209 (2000)

[Publications] Noda,T., et: "BMP Type2 receptor is required for gastrulation and early development of mouse embryos."Dev.Biol.. 221(1). 249-258 (2000)

[Publications] Noda,T., et: "Altered pain responses in mice lacking alpha 1E subunit of the voltage-dependent Ca2+ channel."Proc.Natl.Acad.Sci.USA. 97(11). 6132-6137 (2000)

[Publications] Noda,T., et: "Distribution of Nociceptin/orphanin FQ precursor ptotein and receptor in brain and spinal cord : a study using in situ hybridization and X-gal histochemistry in receptor-deficient mice."J.Comp.Neurol.. 424. 489-508 (2000)

[Publications] Noda,T., et: "Rescue of embryonic lethality in hepatocyte growth factor/scatter factor knockout mice."Genesis. 27. 99-103 (2000)

[Publications] Noda,T., et: "Negative regulation of BMP/Smad signaling by Tobin osteoblasts."Cell. 103. 1085-1097 (2000)

[Publications] Noda,T., et: "Complex phenotype of mice lacking occuldin, a component of tight junction strands."Mol.Biol.Cell. 11. 4131-4142 (2000)

[Publications] Noda,T., et: "Requirement of Runx1/AML1/PEBP2 α B for the generation of hematopoietic cells from endothelial cells."Genes to Cells. (in press). (2000)

[Publications] Noda,T., et: "ASK1 is required for sustained activations of JNK/p38 MAP kinase and apoptosis."EMBO Rep.. (in press). (2000)

[Publications] Takano,H., et: "Impairment of antigen-presenting cell function in mice lacking expression of OX40 ligand."J.Exp.Med.. 191(2). 365-374 (2000)

[Publications] Takano,H., et: "Mmh/Ogg1 gene inactivation results in accumulation of 8-hydroxyguanine in mice."Proc.Natl.Acad.Sci.USA. 87(8). 4156-4161 (2000)

[Publications] Suzuki,A., et: "Colorectal carcinomas in mice lacking the catalytic subunit of PI(3)K gammma."Nature. 406. 897-902 (2000)

[Publications] Suzuki,A., et: "High incidence of breast and endometrial neoplasia resembling human Cowden syndrome in pten+/- mice."Cancer Res.. 60. 3605-3611 (2000)

[Publications] Suzuki,A., et: "Function of PI3K gamma in thymocyte development, T cell activation, and neutrophilmigration."Science. 287. 1040-1046 (2000)

[Publications] Kamijo,T., et: "An increase in circulating mast cell colony-forming cells in asthma."J.Immunol.. (in press). (2000)

[Publications] Kamijo,T., et: "A Novel missense mutation (Tyr88 to Cys) in the platlet membrane : glycoprotein 1bbeta gene affects the expression of GP1b/1X complex."Thrombosis and Haenostasis. (in press). (2000)

[Publications] Kamijo,T., et: "Related Articles Thrombopoietin enhances neutrophil production by bone marrow hematopoietic progenitors with the aid of stem cell factor in congenital neutropenia."J.Leukoc.Biol.. 68. 137-143 (2000)

[Publications] Kamijo,T., et: "Related Articles Retinoic acid is a negative regulator for the differentiation of cord blood-derived human mast cell progenitors."Blood. 95. 2821-2828 (2000)

野田哲生東北大学, 大学院・医学系研究科, 教授 (10183550)