P53 PROTEIN/PROTEIN INTERACTIONS

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DESCRIPTION: (adapted from the investigator's abstract) The p53 tumor suppressor protein is a sequence-specific transcription factor originally discovered in cells transformed by DNA tumor viruses. p53 is expressed in normal cells in response to genotoxic stress, but in cancer cells p53 is often inactive due to genetic mutations. The molecular mechanism by which p53 responds to DNA damage has not been deciphered. What is known is that genotoxic stress leads to increased levels of p53 protein without any effect on p53 mRNA levels and that the response of p53 to specific DNA damaging agents, such as ionizing radiation, requires ATM, the gene that is mutated in patients with ataxia telangiectasia (AT). In Preliminary Results the P.I. provides evidence for a novel interaction between p53 and 14-3.3. Binding of 14-3-3 to p53 is induced by ionizing radiation, is dependent on a wild-type ATM gene and enhances the affinity of p53 for sequence-specific DNA. These findings lead the applicant to the hypothesis that the ATM-dependent molecular mechanism by which p53 responds to genotoxic stress involves 14-3-3 proteins. To test this hypothesis they will: Perform a Structure-Function Analysis of the p53/14-3-3 Interaction. Examine the Physiological Significance of the p53/14-3-3 Interaction in Tissue Culture Cells. Examine the Physiological Significance of the p53-14-3-3 Interaction in Vivo using Homozygous Gene-Targeted Mice. These experiments will establish the physiological significance of the observed interaction between p53 and 14-3-3 and will promote the understanding regarding the regulation of p53 function by DNA damage. The P.I. s long-term goal is to contribute to the elucidation of the molecular mechanism(s) by which p53 activity is induced following DNA damage. The significance of these studies relates to the critical role that p53 has for the response of cancer patients to therapy, since current cancer therapy utilizes primarily DNA damaging agents in the form of radiation or chemotherapeutics.