p53 binds to and is required for the repression of Arf tumor suppressor by HDAC and polycomb.

Authors:
Dr. Xin-Hai Pei, PhD
Dr. Xin-Hai Pei, PhD
University of Miami Miller School of Medicine
Associate Professor
Miami, FL | United States

Cancer Res 2011 Apr 29;71(7):2781-92. Epub 2011 Mar 29.

Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

The expression of tumor suppressor Arf is tightly repressed during normal cell growth at a young age and is activated by oncogenic insults, and during aging, results in p53 activation and cell-cycle arrest to prevent hyperproliferation. The mechanisms of both transcriptional repression and activation of Arf are not understood. We show that p53 binds to and represses Arf expression and that this repression requires the function of both histone deacetylases (HDAC) and polycomb group (PcG) proteins. Inactivation of p53 leads to increased Arf transcription in both mouse embryonic fibroblasts (MEF) cultured in vitro and in tissues and organs of p53 null mice. Activation of endogenous p53 enhances Arf repression, and reintroduction of p53 back into p53 null MEFs restores Arf repression. Both DNA binding and transactivation activities of p53 are required for Arf repression. We show that p53 is required for both HDAC and PcG to repress Arf expression. Bindings of both HDAC and PcG to Arf are disrupted by inactivation of p53 and can be restored in p53 null MEFs by the reintroduction of wild-type, but not mutant, p53. These results indicate that p53 recruits both HDAC and PcG to Arf locus to repress its expression, and this repression constitutes a second feedback loop in p53 regulation.

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Source
http://dx.doi.org/10.1158/0008-5472.CAN-10-3483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3227421PMC
April 2011
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