1997 Fiscal Year Annual Research Report

基本転写因子異常による造血幹細胞腫瘍化の機構の解析

Research Project

Project/Area Number	09250204
Research Institution	The University of Tokyo
Principal Investigator	三谷絹子東京大学, 医学部・付属病院, 助手 (50251244)
Co-Investigator(Kenkyū-buntansha)	小川誠司東京大学, 医学部・付属病院, 助手 (60292900) 本田浩章東京大学, 医学部・付属病院, 助手 (40245064) 千葉滋東京大学, 医学部・付属病院, 助手 (60212049)
Keywords	RNAポリメラーゼII伸長因子 / MEN / t(11;19) / 白血病 / AP‐1活性 / 転写伸長因子
Research Abstract	進展期MDS症例に観察されるt(11;19)(q23;p13.1)の分子解析を行うことにより、新規融合遺伝子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、MENは基本転写因子RNAポリメラーゼII伸長因子をコードしている。MENに対するポリタロ-ナル抗体を作成し、MENが80kDの蛋白質として核内に発現していることを明らかにした。基本転写因子MENの異常発現が白血病発症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、形態学的変化は観察されていないものの、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を失った欠失変異体では観察されなかった。また、MENを発現しているRat1細胞ではmock細胞に比較してFOS蛋白質の発現が亢進していた。さらに、TRE siteをプロモーター領域に有するレポーターを用いたルシフェラーゼ・アッセイの結果、MENを発現しているRat1細胞ではAP‐1活性が亢進していることが明らかになった。これらの効果はすべてMENのlysine‐rich domainに依存性があった。run‐Off assayにより、MENはlysine‐rich domain依存性にfos遺伝子に対する転写伸長を活性化することが明らかになり、これがFOS蛋白質発現の亢進の原因であると考えられた。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: "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 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)
[Publications] Ueno H: "c‐Cbl is tyrosine‐phosphory lated by interleukin‐4 and enhances mitogenic and survival signals of interleukin‐4 receptor by linking with the phosphatidylinositol 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 Rat1 cells with dependence on the lysine‐rich region" J Biol.Chem. 27. 5248-5252 (1998)

1997 Fiscal Year Annual Research Report

基本転写因子異常による造血幹細胞腫瘍化の機構の解析

Principal Investigator

三谷 絹子 東京大学, 医学部・付属病院, 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: "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 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)

[Publications] Ueno H: "c‐Cbl is tyrosine‐phosphory lated by interleukin‐4 and enhances mitogenic and survival signals of interleukin‐4 receptor by linking with the phosphatidylinositol 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 Rat1 cells with dependence on the lysine‐rich region" J Biol.Chem. 27. 5248-5252 (1998)

三谷絹子東京大学, 医学部・付属病院, 助手 (50251244)