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Takahashi, K, Yoshida, N, Murakami, N, Kawata, K, Ishizaki, H, Tanaka-Okamoto, M, Miyoshi, J, Zinn, AR, Shime, H and Inoue, N (2007) Dynamic regulation of p53 subnuclear localization and senescence by MORC3. Mol. Biol. Cell 18:1701-9
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.
Animals; Antigens, Nuclear/metabolism; Autoantigens/metabolism; Cell Aging; Cell Line; Cell Nucleus/metabolism; 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; Nuclear Proteins/metabolism; Recombinant Fusion Proteins/genetics; Recombinant Fusion Proteins/metabolism; Transfection; Tumor Suppressor Protein p53/deficiency; Tumor Suppressor Protein p53/genetics; Tumor Suppressor Protein p53/metabolism
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