Regulation of IAP (Inhibitor of Apoptosis) Gene Expression by the p53 Tumor Suppressor Protein.

摘要

This research proposal sought to utilize information on p53- dependent programmed cell death toward the design of more effective avenues of breast cancer therapy. Key findings in the past three years included our - - finding that a common polymorphism in the p53 tumor suppressor protein influences the ability of this protein to induce cell death. Specifically, the arginine 72 form of p53 induces cell death over fifteen-fold better than the proline 72 form. As the latter form is the exclusive form used for gene therapy, these findings have direct implications for this field. We found by mass spectrometry that the arginine 72 form of p53 interacts with the mitochondrial protein BAK. Molecular modeling of the p53-BAK interaction has led to the identification of a 'BH3-like' domain in p53 (residues 278-289); mutation of residues in this domain abrogates the ability of p53 to oligomerize BAK. These findings will be extended with the creation of peptidomimetics for this domain of p53, with the goal of effecting increased apoptosis of tumor cells.