The p53 tumor-suppressor gene is an important factor in the ability of a cell to maintain genomic integrity and control growth in response to a variety of stresses. The ability of p53 to transcriptionally activate an array of genes in response to damage has been well characterized. However, there is growing evidence that p53 can also function as a transcriptional repressor and that this function may be involved in apoptosis. Currently, only a handful of down-regulated genes have been identified and the mechanism by which p53 transrepresses remains unclear. To add to our understanding of this potentially important function of p53, we have identified two novel targets, stathmin and FKBP25. Upon induction of p53, both genes display decreased levels of endogenous expression in a p53-dependent and specific manner in a number of human and murine cell lines. Furthermore, stathmin was utilized as a molecular marker to investigate a possible mechanism of this down-regulation. We have found that repression of stathmin is mostly relieved by treatment with trichostatin A, an inhibitor of histone deacetylases. This observation provides a functional link between p53-mediated repression and a bona fide repression complex which includes HDAC1 and mSin3a. In support of this potential link, we have shown that p53 associates in vivo with HDAC1 indirectly through mSin3a. In addition, the regions responsible for p53-mSin3a interaction have been initially mapped in vitro to the PAH2-3 region of mSin3a and two regions of p53 previously shown to be involved in repression---the tetramerization and proline domains. Interestingly, the proline domain has been recently shown to be an important component of p53-dependent apoptosis. Finally, we provide evidence that p53 and mSin3a are inducibly targeted to the stathmin promotor and may affect the acetylation status of the region. In conclusion, our data strongly suggest that p53 may repress transcription by recruitment of a repression complex to the promotors of target genes.
Adviser: Donna George. Thesis (Ph.D. in Cell and Molecular Biology) -- University of Pennsylvania, 1999. Includes bibliographical references.