2007 Fiscal Year Final Research Report Summary
Functional in vivo and in vitro analysis of MORC3, which regulates nuclear domain
Project/Area Number |
18590281
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Research Category |
Grant-in-Aid for Scientific Research (C)
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Allocation Type | Single-year Grants |
Section | 一般 |
Research Field |
General medical chemistry
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Research Institution | Research Institute, Osaka Medical Center for Cancer and Cardiovascular Disaeses |
Principal Investigator |
INOUE Norimitsu Research Institute, Osaka Medical Center for Cancer and Cardiovascular Disaeses, Osaka Medical Center for Cancer and Cardiovascular Diseases, Group Head (80252708)
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Project Period (FY) |
2006 – 2007
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Keywords | Leukemia / MORC3 / PML nuclear body / Hematopoiesis / Transcriptional regulation |
Research Abstract |
Acute promyelocytic leukemia(APL) is caused by the expression of the PML/RARA fusion gene in hematopoietic cells. PML encodes a protein that is involved in the formation of the nuclear subdomains, PML-nuclear bodies(NBs) and recruits many proteins such as tumor suppressor p53 into PML-NBs to regulate the transcription. The expression of PML/RARA fusion protein disrupts PML-NBs in APL. However, Pml knockout mice do not develop abnormal hematopoiesis or leukemia. We have shown that MORC3 localizes in PML-NBs in a manner dependent on GHL-ATPase at its amino-terminus and regulates the localization and transcriptional activity of p53(Mol. Biol. Cell 18, 1701-1709, 2007) . To analyze functions of MORC3 in vivo, we have generates Morc3 -/- mice. All Morc3 -/- mice died at birth or within a day. Morc3 +/+, +/- and -/- embryos at 18.5 days postcoitum(dpc) were present at almost the expected Mendelian ratio. Morc3 -/- mice presented with hepatomegaly by the infiltration of Gr-1 and Mac-1 double positive myeloid cells around vessels and small thymus at 18.5 dpc embryo. To characterize the abnormal hematopoiesis in Morc3-/-, we transplanted 14.5 dpc Morc3 -/- or +/+ fetal liver cells into lethally irradiated syngeneic mice. About two months after transplantation, the Morc3 -/- fetal liver transplanted mice presented with dermal inflammation and had more Gr-1 and Mac-1 double positive myeloid cells in skin, spleen and liver than the wild type transplanted mice. The differentiation of these myeloid cells into mature macrophage was impaired. The deficiency of MORC3 induced immature myeloid cells characterized by c-Kit expression. We presented these results in 66the annual meeting of the Japanese cancer association and are preparing the paper.
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Research Products
(13 results)