Site-specific post-translational modifications of human tumor suppressor p53 induced by stress play an important role in the activity of p53 as a transcription factor that regulates cell cycle arrest, senescence or apoptosis. The Iong-term goal of this Project 2, as a part of the PPG, is to seek mechanistic understanding of the molecular interactions and regulation of p53 in human biology and cancer. While multiple acetylation and methylation sites in p53 have been reported, specific effects of individual or combined modifications 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 required for target gene transcriptional activation. Our study specifically supports the notion that p53 recruitment of the co-activator CBP (CREB binding protein) requires association of the CBP bromodomain with p53 at acetylated lys[353]: a molecular interaction that is essential for p53-induced transcriptional activation of the cyclin-dependent kinase inhibitor p21, involved in (31 cell cycle arrest. We hypothesize therefore that distinct modifications of p53 including lysine acetylation and merhylation have differential effects on p53 functions in cells. We propose a multifaceted approach to address mechanistic underpinnings of p53 transcriptional activation with the emphasis on the role of post-translational modifications in p53 activation.
The specific aims are (1) to elucidate molecular basis of these modification mediated molecular interactions of p53 with co-activators, and to develop small molecule chemical probes with structure-based design to functionally modulate p53 interactions;and (2) to determine the interplay between the co-activators CBP/p300 and p53 C-terminal domain in transcriptional regulation and tumor suppression of p53 using a variety of biochemical and cell biological approaches including the establishment of an in vivo model. The emerging results from our planned studies are expected to yield new mechanistic understanding of post-translational 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.

Public Health Relevance

This Project aims to understand the molecular interactions and regulation of human tumor suppressor p53 in human biology of health and cancer;and new findings emerging from the planned study will lead to possible novel cancer therapies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA080058-15
Application #
8678850
Study Section
Special Emphasis Panel (ZCA1-GRB-S)
Project Start
Project End
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
15
Fiscal Year
2014
Total Cost
$268,957
Indirect Cost
$75,038
Name
Icahn School of Medicine at Mount Sinai
Department
Type
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Pappas, Kyrie; Xu, Jia; Zairis, Sakellarios et al. (2017) p53 Maintains Baseline Expression of Multiple Tumor Suppressor Genes. Mol Cancer Res 15:1051-1062
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
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
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
Meslamani, Jamel; Smith, Steven G; Sanchez, Roberto et al. (2016) Structural features and inhibitors of bromodomains. Drug Discov Today Technol 19:3-15
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
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

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