Date of Award

1-1-2011

Document Type

Campus Access Dissertation

Department

Biological Sciences

First Advisor

David Reisman

Abstract

p53 is a tumor suppressor protein that plays a role in many cellular processes ranging from cell cycle regulation to apoptosis. The protein's role as a transcription factor has shown that deregulated transcription, whether increased (as with mutant p53 transcription) or decreased (failure to activate transcription of wild type p53), has the potential to contribute to the formation of human cancers. Transcriptional regulation of the p53 gene is important because its inactivation results in the loss of the apoptotic response and/or failure to undergo cell cycle arrest in response to cellular stress or DNA damage. Understanding the transcriptional regulation of the p53 gene can contribute to our understanding of the mechanisms involved in regulating the overall levels of p53 protein. We have identified two transcription factors, RBP-Jkappa and C/EBPbeta-2, which bind to the p53 promoter and regulate p53 transcription. The results indicate that the two proteins bind to the -972/-953 region on the p53 promoter. RBP-Jkappa serves to repress p53 transcription during growth arrest, while C/EBPbeta-2 serves to enhance p53 transcription during the transition from growth arrest to entry into S-phase. These results suggest that both factors may work cooperatively/coordinately to help regulate the activity of p53 throughout the cell cycle. Also, p53 was recently demonstrated to have a bidirectional gene partner, WDR79. We have created a bidirectional expression vector, pLucRLuc, to study these bidirectional gene pairs in order to understand how they function within the genome and how they are regulated, so that we can gain more insight into the roles that divergent transcription plays in the expression and maintenance of protein coding genes. Our results demonstrate that p53 and its bidirectional gene partner, WDR79, are regulated in a similar cell cycle dependent manner and are regulated similarly by specific transcription factors. p53/WDR79 promoter deletion analysis has demonstrated that two, as of yet, unidentified proteins bind to two different regions along the p53 and WDR79 bidirectional promoters. Identification of these two factors could elucidate the roles that these proteins play in regulating the transcriptional activities of the p53/WDR79 genes.

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