Regulation of IAP (Inhibitor of Apoptosis) Gene Expression by the p53 Tumor Suppressor Protein
Annual rept. 1 May 2003-30 Apr 2004
FOX CHASE CANCER CENTER PHILADELPHIA PA
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This proposal focuses on the tumor suppressor protein p53. This work had three goals the first goal was to identify the promoter elements in two genes, survivin and c-IAP2, that confer transcriptional repression by p53. The second was to use these p53-repressible elements in order to create a mutant adenovirus, in which a key gene for viral replication ElA was controlled by p53-repressible elements. The resultant virus should replicate only in cells where p53 was mutated or deleted, but not in normal cells we are poised to test this hypothesis in Year 3. The final goal involved the codon 72 polymorphic variants of p53. We previously found that the Arginine 72 form of p53 R72, a naturally occurring polymorphic variant, has greatly enhanced ability to kill cells Dumont et al., Nat Genet 2003 due to increased mitochondrial localization. In the last progress report we proposed to elucidate the mechanism underlying enhanced cell death by R72 here in we report that this involves direct binding of p53 to the pro-apoptotic protein BAK. A manuscript describing this work is included in the Appendix. Efforts for year 3 will follow up on this finding.
- Genetic Engineering and Molecular Biology
- Medicine and Medical Research