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Dynamic regulation of p53 subnuclear localization and senescence by MORC3.


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.

SUBMITTER: Takahashi K 

PROVIDER: S-EPMC1855011 | biostudies-literature | 2007 May

REPOSITORIES: biostudies-literature

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Dynamic regulation of p53 subnuclear localization and senescence by MORC3.

Takahashi Keiko K   Yoshida Naofumi N   Murakami Naoko N   Kawata Kiyo K   Ishizaki Hiroyuki H   Tanaka-Okamoto Miki M   Miyoshi Jun J   Zinn Andrew R AR   Shime Hiroaki H   Inoue Norimitsu N  

Molecular biology of the cell 20070301 5


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. C  ...[more]

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