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1996 Fiscal Year Final Research Report Summary

Functional analysis of AML1 gene in normal hematopoietic cells and leukemia cells

Research Project

Project/Area Number 07457229
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Hematology
Research InstitutionUniversity of Tokyo

Principal Investigator

HIRAI Hisamaru  University of Tokyo, Hospital, Internal Medicine, Associate Professor, 医学部・附属病院, 助教授 (90181130)

Co-Investigator(Kenkyū-buntansha) KUROKAWA Mineo  University of Tokyo, Hospital, Internal Medicine, Research Staff, 医学部・附属病院, 医員
OGAWA Seishi  University of Tokyo, Hospital, Internal Medicine, Research Staff, 医学部・附属病院, 助手
TANAKA Tomoyuki  University of Tokyo, Hospital, Internal Medicine, Assistant Professor, 医学部・附属病院, 助手 (50227154)
MITANI Kinuko  University of Tokyo, Hospital, Internal Medicine, Assistant Professor, 医学部・附属病院, 助手 (50251244)
Project Period (FY) 1995 – 1996
KeywordsAML1 gene / chromosomal translocation / transcription factor / extracellular signal-regulated kinase / myelogenous leukemias / phosphorylation
Research Abstract

The AML1 gene on chromosome 21 is disrupted in the (8 ; 21) (q22 ; q22) and (3 ; 21) (q26 ; q22) translocations associated with myelogenous leukemias and encodes a transcription factor. From AML1 gene, two representative forms of proteins, AML1a and AML1b, are produced by an alternative splicing. Overexpressed AML1a totally suppresses granulocytic differentiation and stimulates cell proliferation in 32Dc13 murine myeloid cells treated with granulocyte colony-stimulating factor. These effects by AML1a were canceled by the concomitant overexpression of AML1b. Such biological phenomena could be explained by our observations that AML1a, which solely has no effects as a transcriptional regulator, dominantly suppresses transcriptional activation by AML1b, and that AML1a exhibits the higher affinity for DNA-binding than AML1b. These antagonistic actions could be important for leukemogenesis and/or myeloid cell differentiation.
We also investigate the regulatory mechanisms of AML1 functions through signal transduction pathways. AML1 is phosphorylated in vivo on two serine residues within the proline-, serine- and threonine-rich region, with dependence on the activation of extracellular signal-regulated kinase (ERK). These in vivo phosphorylation sites of AML1 were directly phosphorylated in vitro by ERK.Although alterations in the DNA-binding affinity were not observed between wild AML1 and non-phosphorylated mutants, we have shown that ERK-dependent phosphorylation potentiates the transactivation ability of AML1. Furthermore the phosphorylation site-mutations reduced the transforming capacity of AML1 in fibroblast cells. These data suggest that AML1 functions are regulated by ERK which is activated by cytokine or growth facotr-stimuli. This study would give important clues to clarify unidentified facets of regulatory mechanisms of AML1 function.

  • Research Products

    (12 results)

All Other

All Publications (12 results)

  • [Publications] Kurokawa M: "Overexpression of the human AML1b proto-oncoprotein leads to neoplastic transformation of NIH3T3 cells." Oncogene. 12. 883-892 (1996)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Yamagata T: "Molecular cloning of a novel IRF family transcription factor,ICSAT/Pip/LSIRF,that negatively regulates the activity of the interferon-regulated genes." Mol.Cell.Biol.16. 1283-1294 (1996)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Nakamoto T: "Direct binding of C-terminal region of p130Cas to SH2 and SH3 domains of Src kinase." J.Biol.Chem.271. 8959-8965 (1996)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Ogawa S: "Structurally altered Evi-1 transcript is generated by inv (3)(q21q26) in a cell line derived from chronic myelocytic leukemias in blastic crisis." Oncogene. 13. 183-192 (1996)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Tanaka T: "The extracellular signal-regulated kinase pathway phosphorylates AML1,an acute myeloid leukemia gene product,and potentially regulates its transactivation ability." Mol.Cell.Biol.16. 3967-3979 (1996)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kurokawa M: "A conserved cysteine residue in the runt homology domain of AML1 is required for the DNA-binding activity and the transforming activity on fibroblasts." J.Biol.Chem.271. 16870-16876 (1996)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kurokawa M,Tanaka T,Tanaka K,Ogawa S,Mitani K,Yazaki Y,Hirai H.: "Overexpression of the human AML1b proto-oncoprotein leads to neoplastic transformation of NIH3T3 cells" Oncogene. 12. 883-892 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Yamagata T,Nishida J,Tanaka T,Sakai R,Mitani K,Yoshida M,Taniguchi T,Yazaki Y,Hirai H.: "Molecular cloning of a novel IRF family transcription factor, ICSAT/Pip/LSIRF,that negatively regulated the activity of the interferon-regulated genes" Mol.Cell.Biol.16. 1283-1294 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Nakamoto T,Sakai R,Ozawa K,Yazaki Y,Hirai H.: "Direct binding of C-terminal region of p130Cas to SH2 and Sh3 domains of Src kinase" J.Biol.Chem.271. 8959-8965 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Ogawa S,Yazaki Y,Hirai H.: "Structurally altered Evi-w transcript is generated by inv (3) (q21q26) in a cell line derived from chronic myelocytic leukemias in blastic crisis" Oncogene. 13. 183-192 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Tanaka T,Kurokawa M,Ueki K,Tanaka K,Imai Y,Mitani K,Yzaki Y,Shibata Y,Kadowaki T,Hirai H.: "The extracellular signal-regulated kinase pathway phosphorylates AML1, an acute myeloid leukemia gene product, and potentially regulates its transactivation ability" Mol.Cell.Biol.16. 3967-3979 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kurokawa M,Tanaka T,Tanaka K,Hirano N,Ogawa S,Mitani K,Yazaki Y,Hirai H.: "A conserved cysteine residue in the runt homology domain of AML1 is required for the DNA-binding activity and the transforming activity on fibroblasts" J.Biol.Chem.271. 16870-16876 (1996)

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 1999-03-09  

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