The long-term objective of this project is to understand the molecular mechanisms involved in the regulation of tumor suppressor p53. Upon DNA damage, p53 functions as a transcriptional factor and induces growth arrest or apoptosis. The p53 protein stability and activity are modulated mainly through post-translational modifications. We uncovered that p53 is phosphorylated at Thr55 by TAF1 and this phosphorylation promotes proteasome-mediated degradation of p53. TAF1 is the largest subunit of transcription factor TFIID and is also a cell cycle regulatory protein important for progression through the G1 phase. Thr55 phosphorylation contributes to TAF1-induced cell G1 progression. As a transcription factor, however, TAF1 also contributes to p53-mediated transcriptional activation. Upon DNA damage, K373/K382 diacetyl-p53 directly interacts with the double-bromodomain of TAF1 and recruits TAF1 to p21 promoter independent of other subunits of TFIID, leading to p21 activation. To understand the interplay between p53 and TAF1, we found that TAF1 phosphorylates p53 at Thr55 on the p21 promoter and inhibits p53-mediated transcription. These results led us to propose that, presumably at a later time after DNA damage, TAF1 marks p53 for inactivation via Thr55 phosphorylation, thus turning off of p53-mediated transcription. For this competitive renewal, we seek funding to continue our analysis of the interplay between p53 and TAF1. In particular, the first specific aim continues to investigate the role of the diacetyl-p53/TAF1 double-bromodomain interaction in recruitment of TFIID to p21 promoter. The second specific aim explores the molecular switches for Thr55 phosphorylation on the p21 promoter upon DNA damage and defines the mechanisms underlying the turning off of p53-mediated transcription. The third specific aim studies the requirement of TAF1 double-bromodomain in gene expression genome wide and in p53-mediated transcription upon DNA damage.
|Wu, Yong; Zhou, Hillary; Wu, Ke et al. (2014) PTEN phosphorylation and nuclear export mediate free fatty acid-induced oxidative stress. Antioxid Redox Signal 20:1382-95|
|Wu, Yong; Lin, Joy C; Piluso, Landon G et al. (2014) Phosphorylation of p53 by TAF1 inactivates p53-dependent transcription in the DNA damage response. Mol Cell 53:63-74|
|Nobumori, Yumiko; Shouse, Geoffrey P; Wu, Yong et al. (2013) B56Î³ tumor-associated mutations provide new mechanisms for B56Î³-PP2A tumor suppressor activity. Mol Cancer Res 11:995-1003|
|Shouse, G P; Nobumori, Y; Panowicz, M J et al. (2011) ATM-mediated phosphorylation activates the tumor-suppressive function of B56Ã½Ã½-PP2A. Oncogene 30:3755-65|
|Shouse, G P; Nobumori, Y; Liu, X (2010) A B56gamma mutation in lung cancer disrupts the p53-dependent tumor-suppressor function of protein phosphatase 2A. Oncogene 29:3933-41|
|Maeda, Yutaka; Hwang-Verslues, Wendy W; Wei, Gang et al. (2006) Tumour suppressor p53 down-regulates the expression of the human hepatocyte nuclear factor 4alpha (HNF4alpha) gene. Biochem J 400:303-13|