The effects of genotoxic stress on the p53/p21wafl/cip1 response
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AbstractThe p53 tumor suppressor protein is the central component of the cellular response to genotoxic stress. Due to the prevalence of p53 mutations in numerous human cancers, the study of the activation, and function of this protein is critical to understanding the mechanisms underlying cellular proliferation, and growth. The critical role of p53 hinges on its capacity to integrate signals from different stress induced pathways, and coordinate protective measures resulting in arrest, repair, or apoptosis. Primarily, p53 functions in the expression of genes, and though it can participate in transcription independent interactions, the most common indicator of p53 activity is the upregulation of the p2iwafl/cipl target protein (heretofore referred to as p21). p21 has been established as a hallmark of p53 functioning, and as a direct consequence of p53 transcriptional activity, in response to stress. p21 functions as a positive and negative regulator of cellular progression, and has a role in both Gi and G2 arrest, repair, and apoptosis. It is widely accepted that though signal transduction to p53, is dependent on the nature of stress, the subsequent functioning of the tumor suppressor, in the upregulation of target proteins, such as p21, is comparable and independent of the specific genotoxic stressor. In the present study, the classic p53/p21 paradigm is re-examined in response to differing genotoxic stressors, in normal human lymphoblasts. The results presented within this dissertation demonstrate that p53 transcriptional activation of p21 is specific to type of stress. Furthermore, despite comparable activation, p53 can discriminate between promoters depending on the nature of stress. Moreover, p53 promoter occupancy has direct consequences on histone acetylation, and target gene expression. Importantly, the effect of the differential expression, has consequences on the cellular outcome. The findings presented here demonstrate that the nature of genotoxic stress has a distinct impact on the p53/p21 response in normal human cells, and may be a mechanism underlying p53's role in determining the cellular outcome. The differential p53 transcriptional activity observed in these cells, has implications on the treatment of hematopoietic cancers, and provides an attractive model system for further study of p53 and p21 functions.
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