TY - JOUR
T1 - Dynamic regulation of p53 subnuclear localization and senescence by MORC3
AU - Takahashi, Keiko
AU - Yoshida, Naofumi
AU - Murakami, Naoko
AU - Kawata, Kiyo
AU - Ishizaki, Hiroyuki
AU - Tanaka-Okamoto, Miki
AU - Miyoshi, Jun
AU - Zinn, Andrew R.
AU - Shime, Hiroaki
AU - Inoue, Norimitsu
PY - 2007/5
Y1 - 2007/5
N2 - 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-l- fibroblasts. Conversely, genotoxic stress-induced phosphorylation and stabilization of p53 but barely increased its transcriptional activity in Morc3-l- 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.
AB - 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-l- fibroblasts. Conversely, genotoxic stress-induced phosphorylation and stabilization of p53 but barely increased its transcriptional activity in Morc3-l- 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.
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U2 - 10.1091/mbc.E06-08-0747
DO - 10.1091/mbc.E06-08-0747
M3 - Article
C2 - 17332504
AN - SCOPUS:34248138434
SN - 1059-1524
VL - 18
SP - 1701
EP - 1709
JO - Molecular biology of the cell
JF - Molecular biology of the cell
IS - 5
ER -