Mechanisms of p53-Mediated Apoptosis
Annual summary 20 Feb 2005-19 Feb 2006
ALABAMA UNIV IN BIRMINGHAM
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The p53 tumor suppressor is the most commonly mutated gene in human breast cancer. Upon genotoxic stress, p53, a sequence-specific transcription factor, induces target genes that mediate many cellular activities such as cell cycle arrest and apoptosis. While the mechanism by which p53 induces apoptosis is unclear, this pathway has rich potential as a target for cancer therapies. Thus, the purpose, of this proposal is to characterize the molecular basis of p53- mediated apoptosis by characterizing the transcriptional regulation of IGFBP3, a pro-apoptotic target gene of p53, and by characterizing the role of IGFBP3 in p53-dependent apoptosis. To date, I have found that the N-terminal transcriptional activation domain 1 AD1 and the C-terminal basic domain BD of p53 is inhibitory, while activation domain 2 AD2 is required for transactivation of IGFBP3 by p53. Interestingly, lack of AD1 and the BD is paralleled in nature, and the naturally occurring p53 isoforms activate the IGFBP3 promoter. In addition, inhibition of histone deacetylase activity restores the induction of IGFBP3 by full length p53. Since histone deacetylase HDAC inhibitors are in clinical trials for cancer therapies, my results shed insight into how HDAC inhibitors may be used as breast cancer therapies.
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