Faculty and Staff
College of Arts and Sciences
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The p53 protein is an important tumor suppressor that is associated with many cellular processes including, regulation of the cell cycle, DNA repair, transcriptional regulation of genes, chromosomal segregation, cell senescence, and apoptosis. p53 has the ability to maintain stability of the genome through the induction of numerous crucial genes in response to DNA damage and other stresses to the cell. The expression of p53 is tightly regulated, and induced in early S-phase. This serves as a mechanism to ensure genomic stability prior to cells entering S-phase, and to ensure that the protein is rapidly induced in response to DNA damage. In addition to increased protein stability, the level of p53 protein is ultimately regulated via transcription of the p53 gene and in many human cancers, p53 transcription is deregulated, whether it be increased (as in the case with mutant p53 transcription) or decreased (failure to activate transcription of wild type p53), and can contribute to tumorigenesis. Recently, two genes located near the p53 gene and positioned in the opposite orientation have been identified. The most well studied to date, termed Wrap53, partially overlaps the first exon of p53 and encodes an antisense transcript that regulates p53 post-transcriptionally. A second gene that appears to originate transcription from a site less than 1000bp from the p53 start site is referred to as Wrap53β or WDR79. The origin of multiple transcripts from this region appears to be complicated however we have shown that p53 and Wrap53β can be regulated by the binding of the same transcription factors to a shared bidirectional promoter. These transcription factors appear to bind to the p53 promoter and control its expression, but in doing so, also control the expression of the Wrap53β gene. These results indicate that the orientation of the transcription factor binding sites on this bidirectional regulatory region are not important, and that the factors appear capable of binding to, and regulating the expression of both genes. This type of orientation-independent activity is similar to that which is seen with transcriptional enhancers, in which the orientation of the enhancer sequence does not affect the binding to its specific activator proteins or its activity.
In another aspect of our research we are working to identify small molecules that would selectively inhibit formation of the HIV Tat and cellular p53 complex. Evidence in the literature as well as our preliminary evidence indicate that Tat binds to p53 and inhibits p53’s functions. Preventing the p53-Tat complex is hypothesized to release active p53 and drive cells to undergo apoptosis via a p53-mediated pathway. In virus infected cells, this may thereby effectively prevent replication and maturation of the virus. The identification of lead compounds by screening large compound libraries will allow us to generate new tools that would enable us to further test this hypothesis and develop this line of research. Since individuals on antiretroviral therapy often exhibit persistent low-level viremia, and in some cases active viral replication can be induced, these results could impact new strategies in the development of antiviral compounds.
Reisman, D., Gibson, A., Patel, M., and Wang, Y. 2016. Evidence for a role of a lncRNA encoded from the p53 tumor suppressor gene in maintaining the undifferentiated state of human myeloid leukemias. Gene Reports. 5, 45-50.
Reisman, D and Polson-Zeigler, A. 2015. The bi-directional nature of the promoter of the p53 tumor suppressor gene. J. Leukemia. 3, 3-7
Polson, A. and Reisman, D. 2014. The bidirectional p53-WDR79 promoter is controlled by common cis- and trans-regulatory elements. Gene. 538, 138-149.
Reisman, D. 2013. Transcriptional activation of the p53 tumor suppressor gene provides a rapid protective mechanism against DNA damage during S-phase of the cell cycle. J. Leukemia. 1, 3-8
Reisman, D., Takahashi, P., Polson, A., and Boggs, K. 2012. Transcriptional Regulation of the p53 Tumor Suppressor Gene in S-Phase of the Cell-Cycle and the Cellular Response to DNA Damage. Biochemistry Research International. vol. 2012; Article ID 808934.
Polson, A., Durrett, E., and Reisman, D. 2011. A bidirectional promoter reporter vector for the analysis of the p53/WDR79 dual regulatory element. Plasmid. 66, 169-179.
Takahashi, P., Polson, A. and Reisman, D. 2011. Elevated transcription of the p53 gene in early S-phase leads to a rapid DNA –damage response during S-phase of the cell cycle. Apoptosis. 9, 950-958.
Takahashi, P., Polson, A., and Reisman. D. 2010. p53 response to DNA damage during S-phase. Nature Proceedings. . http://hdl.handle.net/10101/npre.2010.4403.1
Polson, A., Takahashi, P., and Reisman, D. 2010. Chromatin Immunoprecipitation (ChIP) Analysis Demonstrates Coordinated Binding of Two Transcription Factors to the Promoter of the p53 Tumor Suppressor Gene. Cell Bio International. 34; 883-91.
Boggs, K. Henderson, B. and Reisman, D. 2009. The transcription factor RBPk acts to repress p53 transcription in a tissue specific fashion. Cell Biology International. 33; 318-324.
Boggs, K. and Reisman, D. 2007. C/EBPbeta participates in regulating transcription of the p53 gene in response to mitogen stimulation. J. Biol. Chem. 282, 7982-7990.
Boggs, K. and Reisman, D. 2005. The induction of p53 transcription prior to DNA synthesis is regulated through a novel regulatory element within the p53 promoter. Oncogene. 15, 555-565.
Reisman, D., Eaton, E., McMillin, D., Doudican, N. and Boggs, K.. 2001. Cloning and characterization of murine upstream sequences reveals additional positive regulatory elements. Gene. 274, 129-137.
Raman, V., Martensen, S.A., Reisman, D., Evron, E., Odenwald, W.F., Jaffee, E., Marks, J. and Sukumar. 2000. Control of p53 transcription by HOXA5 may play a role in breast cancer. Nature. 405, 974-978.