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Vol. 18, Issue 5, 1701-1709, May 2007

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Dynamic Regulation of p53 Subnuclear Localization and Senescence by MORC3

Keiko Takahashi^*,, Naofumi Yoshida^*, Naoko Murakami^*,, Kiyo Kawata^*, Hiroyuki Ishizaki^,||, Miki Tanaka-Okamoto, Jun Miyoshi, Andrew R. Zinn^¶, Hiroaki Shime^*, and Norimitsu Inoue^*

Departments of *Molecular Genetics and Molecular Biology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Osaka 537-8511, Japan; Division of Molecular Biology, Nara Institute of Science and Technology, Ikoma, Nara 630-0101, Japan; ^||Kan Research Institute, Kyoto, Kyoto 600-8815, Japan; and ^¶Department of Internal Medicine and McDermott Center for Human Growth and Development, The University of Texas Southwestern Medical School, Dallas, TX 75390

Submitted August 25, 2006; Revised February 9, 2007; Accepted February 16, 2007
Monitoring Editor: A. Gregory Matera

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.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

Present address: Department of Pediatrics, University of Michigan Health System, Ann Arbor, MI 48109-0656.

Address correspondence to: Norimitsu Inoue (inoue-no{at}mc.pref.osaka.jp).

Abbreviations used: MORC, microrchidia; PML, promyelocytic leukemia; NBs, nuclear bodies; CBP, CRE-binding protein; MEFs, mouse embryonic fibroblasts; SA--Gal, senescence–associated -galactosidase; bp, base pairs; I-P, internal ribosomal entry site-puromycin resistance gene; dpc, days postcoitum; ADR, adriamycin; ATRA, all-trans-retinoic acid.