Identification of PATZ1 transcription factor as a novel interacting partner and regulator of the p53 tumor suppressor protein
Keskin, Nazlı (2014) Identification of PATZ1 transcription factor as a novel interacting partner and regulator of the p53 tumor suppressor protein. [Thesis]
The tumor suppressor p53 is a stress responsive, sequence specific transcription factor that regulates genes controlling the cell cycle, senescence and apoptosis. Mutation and loss of p53 is the most common genetic event in human cancer resulting in the accumulation of different types of tumors such as testicular carcinoma, soft tissue sarcoma and lymphoma. The focus of this study, the PATZ1 transcription factor, has diverse roles in cancer, development and stem cell biology. Besides being a key transcriptional repressor in lymphocyte development, PATZ1 expression is misregulated in different tumor types such as testicular, colorectal and breast cancers. Because both proteins are significant modifiers of human cancer, we aimed to link the PATZ1 protein to p53 function using a biochemical approach. In this study, we discovered that both overexpressed and endogenous p53 and PATZ1 proteins interact. We identified a p53 binding region in the C-terminal domain of the PATZ1 protein. We further delineated the interaction region by generating site directed point mutant PATZ1 variants which do not bind p53. The p53 – PATZ1 interaction is functionally significant as neither p53 nor PATZ1 can bind DNA in the presence of the other factor. We examined the cellular responses controlled by p53 in cells overexpressing PATZ1. Treatment with the DNA damage inducing cytotoxic drug doxorubicin activates p53 related pathways. Overexpression of PATZ1 made cells more resistant to death by doxorubicin treatment. This study documents a novel player in the p53 pathway, a suppressor transcription factor, PATZ1.
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