The long-term objective of this project is to understand molecular mechanisms involved in regulation of the p53 tumor suppressor. Serving as a checkpoint function to monitor DNA damage, p53 plays a critical role in the regulation of cell proliferation, apoptosis and metabolism. As a DNA-sequence- specific transcription factor, p53 activates transcription of a number of target genes, including the cyclin-dependent kinase inhibitor p21. The transcription activity of p53 is regulated through multiple posttranslational modifications. We previously reported that p53 is phosphorylated at Thr55 by TAF1 (the largest subunit of transcription factor TFIID), leading to p53 inactivation. In the present funding cycle, we made two fundamental discoveries directly related to this renewal: 1) TAF1 phosphorylates p53 on the p21 promoter and this phosphorylation leads to dissociation of p53 from the p21 promoter and turning-off of p53 transcription; and 2) cellular ATP level acts as a molecular switch for TAF1-mediated p53 phosphorylation on the p21 promoter. Our working hypothesis is that TAF1 functions as a cellular ATP sensor, allowing p53-dependent transcription to be regulated in response to cellular metabolism alteration. For this competitive renewal, we seek funding to advance our understanding of this ATP-dependent p53 regulation by TAF1 and address its contribution to cancer. In particular, we propose to uncover how TAF1 kinase activity contributes p53 promoter dissociation in Aim 1. We will answer essential question about how TAF1 senses ATP in Aim 2. Finally, we will explore physiological significance of the regulation in diabetes and cancer in Aim 3. Together, these aims will provide our first detailed understanding of regulation of p53 by TAF1 and its role in cancer.
The p53 tumor suppressor plays an important role in the cellular response to DNA damage. The proposed research is designed to elucidate fundamental mechanisms for how TAF1 contributes to turning-off of p53-mediated transcription and the role of this regulation in cancer. These studies should lead to a better understanding of the molecular mechanism of TAF1-mediated p53 regulation in cell growth and in cancer. In addition, because cellular ATP levels control TAF1-mediated p53 phosphorylation, the proposed studies should also provide a new model for regulation of p53 tumor suppressor and potentially a new paradigm for understanding how cell metabolism contributes to cancer.
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