1997 Fiscal Year Annual Research Report

前白血病状態進展にかかわる転写因子異常の解析

Research Project

Project/Area Number	08671215
Research Institution	Tokyo University
Principal Investigator	三谷絹子東京大学, 医学部・附属病院, 助手 (50251244)
Co-Investigator(Kenkyū-buntansha)	黒川峰夫東京大学, 医学部・附属病院, 医員小川誠司東京大学, 医学部・附属病院, 助手 (60292900) 田中智之東京大学, 医学部・附属病院, 助手 (50227154) 平井久丸東京大学, 医学部・附属病院, 助教授 (90181130)
Keywords	RNAポリメラーゼII伸長因子 / 転写伸長因子 / MEN / t(11;19) / 白血病 / AP-1活性
Research Abstract	前白血病状態が白血病化する分子機構の一端を明らかにする目的で進展期MDS症例に観察されるt(11;19)(q23;p13.1)の原因遺伝子MLL/MENのクローニングを行った。MLLはAT hooksと2つのzinc finger domainsを有する転写因子であり、t(11;19)転座の結果、2つのzinc finger domainsを失っていた。一方、MENはRNAポリメラーゼII伸長因了をコードしている新規遺伝子であり、t(11;19)転座の結果、N末の45個のアミノ酸を失っていた。私たちは、MLL/MEN、tMLL(患者白血病細胞で発現が期待される2つのzinc finger domains以下のシークエンスを失った短縮型のMLL)、MENのcDNAをCos7細胞に遺伝子導入し、それぞれ230kD,180kD,80kDの蛋白質として発現することを明らかにした。免疫組織染色及び細胞分画の実験により、これらの蛋白質はすべて主に核内に存在することが明らかになった。従って、核内の転写制御異常が前白血病状態進展に関与すると考えられた。さらに、基本転写因子MENの異常発現が白血病進展に至る機序を明らかにする目的で、MENの造腫瘍活性を以下の実験で証明した。ラットの線維芽細胞Rat1にMENを遺伝子導入すると、コロニー形成能の増強及び血清要求性の低下が観察された。これらの効果はMENのc末領域に存在するlysine-rich domain依存性であった。また、MENを発現しているRat1細胞ではFOS蛋白質の発現亢進及びAP-1活性の亢進が観察された。これらの効果はやはりすべてMENのlysine-rich domainに依存性であった。従って、MENの造腫瘍活性はFOSの発現亢進を介するAP-1活性の増強によるものであることが予測された。

Research Products

(16 results)

All Other

All Publications (16 results)

[Publications] Ogawa S: "Abnormal expression of Evi-1 gene in human leukemias." Human Cell. 9. 323-332 (1997)
[Publications] Ueno H: "Antisense repression of proto-oncogene c-CBL enhances activation of the JAK-STAT pathway but not the Ras pathway in epidermal growth factor receptor signalling." J Biol.Chem. 272. 8739-8743 (1997)
[Publications] Hangaishi A: "Mutations and loss of expression of a mismatch repair gene,hMLH1,in leukemia and lymphoma cell lines." Blood. 89. 1740-1747 (1997)
[Publications] Odai H: "Purification and molecular cloning of SH2-and SH3-containing inositol polyphosphate-5-phosphatase,which is involved in the signaling pathway of granulocyte-macrophage colony-stimulating factor,erythropoietin,and Bcr-Abl." Blood. 89. 2745-2756 (1997)
[Publications] Akiyama N: "Fulminent septicemic syndrome of Bacillus cereus in a leukemic patient." Internal Medicine. 36. 221-226 (1997)
[Publications] Mitani K: "No concomitant occurrence of the N-ras and p53 gene mutations in myelodysplastic syndrome." Leukemia. 11. 863-865 (1997)
[Publications] Ueno H: "c-Cbl is tyrosine-phosphorylated by interleukin-4 and enhances mitogenic and survival signals of interleukin-4 receptor by linking with the phosphatidy linositol 3′ kinase pathway." Blood. 91. 46-53 (1998)
[Publications] Tanaka K: "The AML1/ETO(MTG8)and AML1/Evi-1 leukemia-associated chimeric oncoproteins accumulate PEBP2beta(CBFbeta)in the nucleus more efficiently than wild-type AML1." Blood. (in press).
[Publications] Hosoya N: "Frameshift Mutations of the hMSH6 Gene in Human Leukemia Cell Lines." JJCR. 89. 33-39 (1998)
[Publications] Kanda Y: "Overexpression of the MEN/ELL protein,an RNA polymerase II elongation factor,results in transformation of Ratl cells with dependence on the lysine-rich region." J Biol.Chem. 27. 5248-5252 (1998)
[Publications] Ueno H: "The phosphatidylinositol 3′ kinase pathway is required for the survival of leukocyte tyrosine kinase." Oncogene. 14. 3067-3072 (1997)
[Publications] Yamagata T: "Triple synergism of human T-lymphotropic virus type l-encoded Tax,GATA-binding protein,and AP-1 is required for constitutive expression of the interleukin-5 gene in adult T-cell leukemia cells." Mol.Cell.Biol.17. 4272-4281 (1997)
[Publications] Kanda Y: "Subcellular localization of the MEN,MLL/MEN,and truncated MLL proteins expressed in leukemic cells carrying the t(11;19)(q23;p13.1)translocation." Int J Hematol. 66. 189-195 (1997)
[Publications] Hirai H.: "Recent progress in molecular mechanisms of leukemogenesis : The cyclin-dependent kinase 4-inhibitor gene in human leukemias." Leukemia. 11. 358-360 (1997)
[Publications] Mitani K: "Leukemogenesis by the chromosomal translocatioms." Leukemia. 11. 294-296 (1997)
[Publications] Mitani K: "Molecular mechanism of blastic crisis in chronic myelocytic leukemia." Leukemia. 11. 503-505 (1997)

1997 Fiscal Year Annual Research Report

前白血病状態進展にかかわる転写因子異常の解析

Principal Investigator

三谷 絹子 東京大学, 医学部・附属病院, 助手 (50251244)

Research Products

[Publications] Ogawa S: "Abnormal expression of Evi-1 gene in human leukemias." Human Cell. 9. 323-332 (1997)

[Publications] Ueno H: "Antisense repression of proto-oncogene c-CBL enhances activation of the JAK-STAT pathway but not the Ras pathway in epidermal growth factor receptor signalling." J Biol.Chem. 272. 8739-8743 (1997)

[Publications] Hangaishi A: "Mutations and loss of expression of a mismatch repair gene,hMLH1,in leukemia and lymphoma cell lines." Blood. 89. 1740-1747 (1997)

[Publications] Odai H: "Purification and molecular cloning of SH2-and SH3-containing inositol polyphosphate-5-phosphatase,which is involved in the signaling pathway of granulocyte-macrophage colony-stimulating factor,erythropoietin,and Bcr-Abl." Blood. 89. 2745-2756 (1997)

[Publications] Akiyama N: "Fulminent septicemic syndrome of Bacillus cereus in a leukemic patient." Internal Medicine. 36. 221-226 (1997)

[Publications] Mitani K: "No concomitant occurrence of the N-ras and p53 gene mutations in myelodysplastic syndrome." Leukemia. 11. 863-865 (1997)

[Publications] Ueno H: "c-Cbl is tyrosine-phosphorylated by interleukin-4 and enhances mitogenic and survival signals of interleukin-4 receptor by linking with the phosphatidy linositol 3′ kinase pathway." Blood. 91. 46-53 (1998)

[Publications] Tanaka K: "The AML1/ETO(MTG8)and AML1/Evi-1 leukemia-associated chimeric oncoproteins accumulate PEBP2beta(CBFbeta)in the nucleus more efficiently than wild-type AML1." Blood. (in press).

[Publications] Hosoya N: "Frameshift Mutations of the hMSH6 Gene in Human Leukemia Cell Lines." JJCR. 89. 33-39 (1998)

[Publications] Kanda Y: "Overexpression of the MEN/ELL protein,an RNA polymerase II elongation factor,results in transformation of Ratl cells with dependence on the lysine-rich region." J Biol.Chem. 27. 5248-5252 (1998)

[Publications] Ueno H: "The phosphatidylinositol 3′ kinase pathway is required for the survival of leukocyte tyrosine kinase." Oncogene. 14. 3067-3072 (1997)

[Publications] Yamagata T: "Triple synergism of human T-lymphotropic virus type l-encoded Tax,GATA-binding protein,and AP-1 is required for constitutive expression of the interleukin-5 gene in adult T-cell leukemia cells." Mol.Cell.Biol.17. 4272-4281 (1997)

[Publications] Kanda Y: "Subcellular localization of the MEN,MLL/MEN,and truncated MLL proteins expressed in leukemic cells carrying the t(11;19)(q23;p13.1)translocation." Int J Hematol. 66. 189-195 (1997)

[Publications] Hirai H.: "Recent progress in molecular mechanisms of leukemogenesis : The cyclin-dependent kinase 4-inhibitor gene in human leukemias." Leukemia. 11. 358-360 (1997)

[Publications] Mitani K: "Leukemogenesis by the chromosomal translocatioms." Leukemia. 11. 294-296 (1997)

[Publications] Mitani K: "Molecular mechanism of blastic crisis in chronic myelocytic leukemia." Leukemia. 11. 503-505 (1997)

三谷絹子東京大学, 医学部・附属病院, 助手 (50251244)