Nucleic Acids Research Advance Access originally published online on March 7, 2007
Nucleic Acids Research 2007 35(6):2093-2104; doi:10.1093/nar/gkm099
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Nucleic Acids Research, 2007, Vol. 35, No. 6 2093-2104
© 2007 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Molecular Biology |
Cancer-derived p53 mutants suppress p53-target gene expression—potential mechanism for gain of function of mutant p53
1Laboratory of Molecular Carcinogenesis, National Cancer Centre, 11 Hospital Drive, Singapore 169610, Singapore, 2Department of Biochemistry, National University of Singapore, 10, Kent Ridge Crescent, Singapore 119260 and 3Department of Oncology, Mario Negri Institute for Pharmacological Research, Via Eritrea No 62, 20154 Milan, Italy
*To whom correspondence should be addressed. Tel: +65 6436 8349; Fax: +65 6226 5694; Email: cmrksb{at}nccs.com.sg
Received May 30, 2006. Revised February 4, 2007. Accepted February 5, 2007.
Tumour-derived p53 mutants are thought to have acquired ‘gain-of-function’ properties that contribute to oncogenicity. We have tested the hypothesis that p53 mutants suppress p53-target gene expression, leading to enhanced cellular growth. Silencing of mutant p53 expression in several human cell lines was found to lead to the upregulation of wild-type p53-target genes such as p21, gadd45, PERP and PTEN. The expression of these genes was also suppressed in H1299-based isogenic cell lines expressing various hot-spot p53 mutants, and silencing of mutant p53, but not TAp73, abrogated the suppression. Consistently, these hot-spot p53 mutants were able to suppress a variety of p53-target gene promoters. Analysis using the proto-type p21 promoter construct indicated that the p53-binding sites are dispensable for mutant p53-mediated suppression. However, treatment with the histone deacetylase inhibitor trichostatin-A resulted in relief of mutant p53-mediated suppression, suggesting that mutant p53 may induce hypo-acetylation of target gene promoters leading to the suppressive effects. Finally, we show that stable down-regulation of mutant p53 expression resulted in reduced cellular colony growth in human cancer cells, which was found to be due to the induction of apoptosis. Together, the results demonstrate another mechanism through which p53 mutants could promote cellular growth.
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