Stress-induced C-terminal lysine acetylation of p53 plays an important role in the activity of p53 as a transcription factor that regulates cell cycle arrest, senescence or apoptosis. The long-term goal of this Project is to seek mechanistic understanding of the molecular interactions that regulate the tumor suppressor p53. While multiple acetylation sites in its C-terminal tail have been reported, specific effects of individual or combined acetylation of these lysine residues on p53 activity remain elusive. Preliminary data is presented involving a structure-based functional analysis of p53 supporting the notion that acetylation-induced p53 activation in response to DNA damage is involved in co-activator recruitment and subsequent histone acetylation. This study revealed that p53 recruitment of the co-activator CBP (CREB binding protein) requires association of the conserved bromodomain of CBP with p53 at acetylated lys382: a specific molecular interaction that is essential for p53-induced transcriptional activation of the cyclin-dependent kinase inhibitor p21, involved in G1 cell cycle arrest. We hypothesize that distinct modifications of p53 C-terminal residues, including lysine acetylation and ubiquitination, as well as serine phosphorylation, have differential effects on p53 functions in cells under different conditions. A multifaceted approach is proposed to address mechanistic underpinnings of p53 transcriptional activation with the emphasis on the role of C-terminal post-translational modifications in p53 activation.
The specific aims i nclude (1) to explore the role of C-terminal modifications of p53 in co-activator recruitment using NMR structure-based biochemical analysis (2) to develop small molecule ligands to be used as probes for molecular functions of p53 using NMR-based chemical screening, and finally (3) to elucidate the role of the C-terminus of p53 in its ability to act as a transcription factor using a variety of biochemical and cell biological approaches including the establishment of an in vivo model. The proposed multidisciplinary studies range from structure-based NMR analysis and design of chemical compounds in vitro to functional analyses in cell culture, as well as the use of an in vivo mouse model. The emerging results from the proposed studies are expected to enhance our understanding of the molecular basis of C-terminal modifications in p53 function. Given the central role of p53 in cancer, these studies will have important implications for the prognosis and treatment of human tumors.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
Project #
Application #
Study Section
Subcommittee G - Education (NCI)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Mount Sinai School of Medicine
New York
United States
Zip Code
Pappas, Kyrie; Xu, Jia; Zairis, Sakellarios et al. (2017) p53 Maintains Baseline Expression of Multiple Tumor Suppressor Genes. Mol Cancer Res 15:1051-1062
Mungamuri, Sathish Kumar; Qiao, Rui F; Yao, Shen et al. (2016) USP7 Enforces Heterochromatinization of p53 Target Promoters by Protecting SUV39H1 from MDM2-Mediated Degradation. Cell Rep 14:2528-37
Muñoz-Fontela, César; Mandinova, Anna; Aaronson, Stuart A et al. (2016) Emerging roles of p53 and other tumour-suppressor genes in immune regulation. Nat Rev Immunol 16:741-750
Ou, Yang; Wang, Shang-Jui; Li, Dawei et al. (2016) Activation of SAT1 engages polyamine metabolism with p53-mediated ferroptotic responses. Proc Natl Acad Sci U S A 113:E6806-E6812
Guernet, Alexis; Mungamuri, Sathish Kumar; Cartier, Dorthe et al. (2016) CRISPR-Barcoding for Intratumor Genetic Heterogeneity Modeling and Functional Analysis of Oncogenic Driver Mutations. Mol Cell 63:526-38
Meslamani, Jamel; Smith, Steven G; Sanchez, Roberto et al. (2016) Structural features and inhibitors of bromodomains. Drug Discov Today Technol 19:3-15
Hwang, So-Young; Deng, Xianming; Byun, Sanguine et al. (2016) Direct Targeting of ?-Catenin by a Small Molecule Stimulates Proteasomal Degradation and Suppresses Oncogenic Wnt/?-Catenin Signaling. Cell Rep 16:28-36
Shi, D; Dai, C; Qin, J et al. (2016) Negative regulation of the p300-p53 interplay by DDX24. Oncogene 35:528-36
Tavana, Omid; Li, Dawei; Dai, Chao et al. (2016) HAUSP deubiquitinates and stabilizes N-Myc in neuroblastoma. Nat Med 22:1180-1186
Wang, Donglai; Kon, Ning; Lasso, Gorka et al. (2016) Acetylation-regulated interaction between p53 and SET reveals a widespread regulatory mode. Nature 538:118-122

Showing the most recent 10 out of 101 publications