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Dynamic regulation of p53 subnuclear localization and senescence by MORC3.
- Source :
-
Molecular biology of the cell [Mol Biol Cell] 2007 May; Vol. 18 (5), pp. 1701-9. Date of Electronic Publication: 2007 Mar 01. - Publication Year :
- 2007
-
Abstract
- The tumor suppressor p53 is a key transcriptional factor regulating the induction of cellular senescence by oncogenic signals. The activity of p53 is regulated by recruitment into promyelocytic leukemia (PML)-nuclear bodies (NBs) as well as by stabilization through posttranslational modifications such as phosphorylation and acetylation. Here we found that MORC3 (microrchidia3)-ATPase activated p53 and induced cellular senescence in normal human and mouse fibroblasts but not p53-/- fibroblasts. Conversely, genotoxic stress-induced phosphorylation and stabilization of p53 but barely increased its transcriptional activity in Morc3-/- fibroblasts. MORC3 localized on PML-NBs in presence of PML and mediated recruitment of p53 and CREB-binding protein (CBP) into PML-NBs. In contrast, expression of ATPase activity-deficient mutant MORC3-E35A or siRNA repression of MORC3 impaired the localization of p53 and Sp100 but not CBP on PML-NBs. These results suggest that MORC3 regulates p53 activity and localization into PML-NBs. We identified a new molecular mechanism that regulates the activity of nuclear proteins by localization to a nuclear subdomain.
- Subjects :
- Animals
Antigens, Nuclear metabolism
Autoantigens metabolism
Cell Line
Cell Nucleus metabolism
Cellular Senescence
Cyclin-Dependent Kinase Inhibitor p21 metabolism
Doxorubicin pharmacology
Fibroblasts cytology
Fibroblasts drug effects
Fibroblasts metabolism
Genes, p53
HeLa Cells
Humans
Mice
Mice, Inbred C57BL
Mice, Knockout
Nuclear Proteins deficiency
Nuclear Proteins genetics
Recombinant Fusion Proteins genetics
Recombinant Fusion Proteins metabolism
Transfection
Tumor Suppressor Protein p53 deficiency
Tumor Suppressor Protein p53 genetics
Nuclear Proteins metabolism
Tumor Suppressor Protein p53 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1059-1524
- Volume :
- 18
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Molecular biology of the cell
- Publication Type :
- Academic Journal
- Accession number :
- 17332504
- Full Text :
- https://doi.org/10.1091/mbc.e06-08-0747