2005 Fiscal Year Final Research Report Summary
AML1 complex as a molecular target for leukemia therapy
| Project/Area Number |
15390033
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Biological pharmacy
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| Research Institution | National Cancer Center Research Institute |
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Principal Investigator |
KITABAYASHI Issay National Cancer Center Research Institute, Molecular Oncology Division, Chief, 分子腫瘍学部, 部長 (20261175)
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| Co-Investigator(Kenkyū-buntansha) |
YOSHIDA Hitoshi National Cancer Center Research Institute, Molecular Oncology Division, Section Head, 分子腫瘍学部, 室長 (30303548)
SHIUMIZU Kimiko National Cancer Center Research Institute, Molecular Oncology Division, Senior Researcher, 分子腫瘍学部, 主任研究官 (00161414)
ROKUDAI Susumu National Cancer Center Research Institute, Molecular Oncology Division, Researcher, 分子腫瘍学部, 研究員 (20392334)
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| Project Period (FY) |
2003 – 2005
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| Keywords | Leukemia / MOZ / histone acetyltransferase / hematopoiesis / transcription regulation / AML1 / stem cells / HIPK2 |
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| Research Abstract |
The genes encoding the AML1/CBFβ transcription factor complex are the most frequent targets of chromosome translocations found in human leukemia. We previously purified AML1 complexes, and found that the complex contains histone acetyltransferases such as p300 and MOZ, promyelocytic leukemia isoform I (PML I), and a protein kinase (HIPK2). The genes encoding AML1 and some of the AML1-interacting proteins are the targets of leukemia-associated chromosome translocations, suggesting that common pathways may be shared by distinct myeloid malignancies and underscores the importance of this complex in hematopoiesis and leukemogenesis. HIPK2 formed a complex with AML1 and p300, and phosphorylated both AML1 and p300 to stimulate both transcription activation and HAT activities. Phosphorylation of p300 was triggered by phosphorylated AML1 as well as by PU.1, c-MYB, c-JUN, and c-FOS, and was inhibited by dominant-negative HIPK2. Phosphorylation of p300 and AML1 was impaired in Hipk1/2 double-def
… More
icient mouse embryos. Double-deficient mice exhibited defects in primitive/definitive hematopoiesis, vasculogenesis, angiogenesis and neural tube closure. These phenotypes are in part similar to those observed in p300- and CBP-deficient mice. HIPK2 also phosphorylates another co-activator, MOZ, in an AML1-dependent manner. These results suggest a novel mechanism by which transcription factors could regulate local histone acetylation and transcription of their target genes. To investigate the roles of MOZ in normal hematopoiesis, we generated MOZ-null mice. MOZ^<-/-> mice died around E15. In MOZ^<-/-> E14.5 embryos, hematopoietic stem cells, lineage-committed progenitors and B lineage cells were severely reduced. On the other hand, arrest of erythroid maturation and elevated myeloid lineage populations were observed. MOZ-deficient fetal liver cells could not reconstitute hematopoiesis of recipients after transplantation. Analysis using microarray and flow cytometry revealed that expression of thrombopoietin receptor (c-Mpl), HoxA9 and c-Kit was down-regulated. These results show that MOZ is required for maintenance of hematopoietic stem cells and that it plays a role in differentiation of erythroid and myeloid cells. Less
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[Journal Article] DNA damage-induced phosphorylation of MdmX st serine 367 activates p53 by targeting Mdx for mdm2-dependent degradation.2005
Author(s)
Okamoto K., Kashima K., Pereg Y., Ishida M., Yamazaki S., Nota A., Teunisse A, Migliorini D., Kitabayashi I., Marine JC., Prives C., Shiloh Y., Jochemsen AG., Taya Y.
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Journal Title
Mol. Cell. Biol. 25
Pages: 9608-9620
Description
「研究成果報告書概要(和文)」より
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[Journal Article] Mutations and Deletions of the CBP Gene in Human Lung Cancer.2005
Author(s)
Kishimoto M., Kohno T., Okudela K., Otsuka A., Sasaki H., Tanabe C., Sakiyama T., Hirama C., Kitabayashi I., Minna JD., Takenoshita S., Yokota J.
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Journal Title
Clinical Cancer Research 11
Pages: 512-519
Description
「研究成果報告書概要(和文)」より
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[Journal Article] Mutations and Deletions of the CBP Gene in Human Lung Cancer.2005
Author(s)
Kishimoto M, Kohno T, Okudela K, Otsuka A, Sasaki H.Tanabe C, Sakiyama T, Hirama C, Kitabayashi I, Minna JD, Takenoshita S, Yokota J
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Journal Title
Clinical Cancer Research 11
Pages: 512-519
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] DNA damage-induced phosphorylation of MdmX st serine 367 activates p53 by targeting Mdx for mdm2-dependent degradation.2005
Author(s)
Okamoto, K, Kashima, K, Pereg, Y, Ishida, M, Yamazaki, S.Nota, A, Teunisse, A, Migliorini, D, Kitabayashi, I, Marine, JC, Prives, C, Shiloh, Y, Jochemsen, AG, Taya, Y.
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Journal Title
Mol.Cell.Biol. 25
Pages: 9608-9620
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Rearrangement of the MOZ gene in pediatric therapy-related myelodysplastic syndrome with a novel chromosomal translocation t(2;8)(p23;p11).2003
Author(s)
Imamura, T., Kakazu, N., Hibi, S., Morimoto, A., Fukushima, Y., Ijuin, I., Hada, S., Kitabayashi, I., Abe, T., Imashuku, S.
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Journal Title
Genes Chromosomes Cancer 36
Pages: 413-419
Description
「研究成果報告書概要(欧文)」より
