Mechanisms of p53-Mediated Apoptosis
Abstract
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 breast 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, by 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 I found that the naturally occurring p53 isoforms activate the IGFBP3 promoter. Interestingly, inhibition of histone deacetylase activity restores the induction of IGFBP3 by full length p53. Since hi stone deacetylase (HDAC) inhibitors are currently undergoing clinical trials for cancer therapies, my results shed insight into how HDAC inhibitors may be used as breast cancer therapies.
Document Details
- Document Type
- Technical Report
- Publication Date
- Mar 01, 2005
- Accession Number
- ADA435101
Entities
People
- Kelly L. Mcnaughton
Organizations
- University of Alabama