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A new protein, MORC3,that regulates nuclear localization of proteins, and MORC protein family

调节蛋白质核定位的新蛋白MORC3以及MORC蛋白家族

基本信息

批准号：
16590237
负责人：
INOUE Norimitsu
金额：
$ 1.98万
依托单位：
Osaka Medical Center for Cancer and Cardiovascular Diseases
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16590237/
关键词：
MORC PML bosy Sp100 p53 Nuclear Dynamics GHL-ATPase SUMO

项目摘要

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.

在致癌信号、转录调节、端粒维持和细胞衰老中，蛋白质通过募集到核亚结构域中来调节。我们表明，MORC 3是参与在PML体的蛋白质的条件性或组成性定位。Sp100定位于M0 RC 3表达细胞中的PML-NB中，但在ATP酶缺陷型M0 RC 3突变体（E35 A）表达细胞中和通过shRNA表达的M0 RC 3抑制细胞中分散到整个细胞核中。肿瘤抑制基因p53通过致癌信号被募集到PML-NB中。M0 RC 3的过表达介导p53募集到PML-NB中。在荧光素酶报告基因分析中，MORC 3而不是MORC 3-E35 A增强了p53-转录激活，用于p53-响应元件或p21或Bax的启动子。此外，MORC 3诱导内源性p21表达。此外，我们产生了Morc 3靶向小鼠。所有Morc 3-/-小鼠在出生时或在一天内死亡。Morc 3 +/+、+/-和-/-胚胎在交配后18.5天（dpc）几乎以预期的孟德尔比率存在。我们在14.5 dpc从Morc 3 +/+和-/-胚胎产生小鼠胚胎成纤维细胞（MEF）。在Morc 3-/- MEFs中，p53通过翻译后修饰（包括丝氨酸18和23位的磷酸化）得以稳定，但阿霉素几乎不能激活p53; Morc 3-/-小鼠表现出异常的髓系发育和小胸腺。MORC家族蛋白的新命名（人MORC 1、MORC 2、MORC 3和MORC 4，小鼠MORC 1、MORC 2a、MORC 2b、MORC 3和MORC 4）已被HUGO和MGD所接受。