| Budget Amount *help |
¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 2005: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 2004: ¥1,900,000 (Direct Cost: ¥1,900,000)
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| Research Abstract |
In oncogenic signals, transcriptional regulation, telomere maintenance and cellular senescence, proteins are regulated by recruitment into nuclear subdomains. We show that MORC3 is involved in the conditional or constitutive localization of proteins in PML-body. Sp100 is localized in PML-NBs in MORC3-expressing cells but dispersed into entire nuclei in ATPase-deficient MORC3 mutant (E35A) expressing cells and in MORC3-repressed cells by shRNA expression. The tumor suppressor p53 is recruited into PML-NBs by oncogenic signal. Overexpression of MORC3 mediated p53 recruitment into PML-NBs. MORC3 but not MORC3-E35A enhanced p53-transcriptional activation in luciferase reporter gene analyses for p53-responsive elements, or the promoters of p21 or Bax. In addition, MORC3 induced endogenous p21 expression. Furthermore, we generated Morc3-targeted 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. We generated mouse embryonic fibroblasts (MEFs) from Morc3+/+ and -/- embryos at 14.5 dpc. In Morc3-/- MEFs, p53 was stabilized through posttranslational modification including phosphorylation at serine 18 and 23 but barely activated by the treatment of adriamycin.
Morc3-/- mice showed abnormal development of myeloid lineage and small thymus. In vitro CFU assay by Morc3-/- fetal liver, GM-CSF but not M-CSF mediated development to monocyte.
New nomenclature for MORC family proteins (MORC1,MORC2,MORC3 and MORC4 in human and Morc1,Morc2a, Morc2b, Morc3 and Morc4 in mouse) were proposed by us and accepted in HUGO and MGD.
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