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 cancer therapies. Thus, the purpose, of this proposal is to characterize the molecular basis of p53-mediated apoptosis. Throughout this funding period, 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. Importantly, p53 containing the inhibitory functional domains can be activated to induce IGFBP3 when histone deacetylases (HDACs) are inhibited by HDAC inhibitors. Furthermore, I found that HDAC2 specifically inhibits p53 activity by inhibiting p53-DNA binding activity. 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.
Document Details
- Document Type
- Technical Report
- Publication Date
- Mar 01, 2007
- Accession Number
- ADA468053
Entities
People
- Kelly L. Harms
Organizations
- University of Alabama