Growth Control Regulated by p53 and Mdm2 on Chromatin

Cuny Hunter College, New York NY

Investigators

Abstract

The p53 tumor suppressor is an important transcription factor that has been highly conserved throughout vertebrate evolution. The wild-type p53 protein acts as a controller of cell growth and cell death. The negative feedback regulator of p53, Mdm2, is critically important to sustain development. p53 activates expression of mdm2 and the Mdm2 protein in turn inactivates p53 by either repressing its transcriptional activity or facilitating its degradation by the proteasome. The Bargonetti laboratory and colleagues are among only a few groups that have provided evidence that Mdm2 forms both soluble as well as chromatin-bound complexes with p53 in human cells. Several lines of evidence suggest that this process exemplifies an important basic transcription regulation program where Mdm2 influences the recruitment of factors to chromatin to prevent functional transcription, but this has yet to be fully elucidated. Human cell lines are used to investigate the chemical nature and function of p53-Mdm2 chromatin-associated complexes and their impact on transcription. The Bargonetti group is carrying out basic research in combination with a strong broader impact objective to produce the next generation of multicultural and multiethnic scientists. The core objectives of the project are the following: 1) Determine if Mdm2 blocks transcription initiation or elongation at p53 target genes. 2) Characterize the role of Mdm2 on histone modifications at p53 target genes. 3) Determine if Mdm2 and p300 act as competitors for the p53 transcription factor in Mdm2 over-expression cell culture models. 4) Examine the regulation of chromatin-associated p53 by Mdm2 proteins produced from alternatively spliced mdm2. Based on the results obtained from this project the ability of the alternate forms of Mdm2 to influence p53 transcriptional activity, recruitment of p300 and PCAF, and regulation of local and distal histone modification will be determined. 5) Integrate research and teaching as a method to excite the next generation, multiethnic, science work force. The project being carried out by the Bargonetti laboratory group integrates research and teaching as a method to excite the next generation, multiethnic, science work force. Undergraduate students as well as graduate students are part of the research team. Under-represented minority students, as well as non-minority students, carry out the research and are mentored by Dr. Bargonetti in a multicultural environment where high standards are set for all and mutual respect for all cultures is the expectation. All students participating in this project are encouraged to move on to notable Ph.D. programs, post-doctoral positions and tenure track faculty jobs.