Dynamic regulation of p53 subnuclear localization and senescence by MORC3.
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.
Takahashi
Keiko
K
Department of Molecular Genetics and Molecular Biology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Osaka 537-8511, Japan.
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
D000818:Animals; D034961:Antigens, Nuclear / Q000378:metabolism; D001324:Autoantigens / Q000378:metabolism; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D016922:Cellular Senescence; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016158:Genes, p53; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D034961:Antigens, Nuclear; D001324:Autoantigens; D050759:Cyclin-Dependent Kinase Inhibitor p21; C513310:MORC1 protein, human; C120546:Morc1 protein, mouse; D009687:Nuclear Proteins; D011993:Recombinant Fusion Proteins; C092315:Sp100 protein, mouse; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C066642:SP100 protein, human; D004317:Doxorubicin