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 #
5P01CA080058-14
Application #
8531166
Study Section
Special Emphasis Panel (ZCA1-GRB-S)
Project Start
Project End
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
14
Fiscal Year
2013
Total Cost
$261,477
Indirect Cost
$72,736
Name
Icahn School of Medicine at Mount Sinai
Department
Type
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
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Hager, Kayla M; Gu, Wei (2014) Understanding the non-canonical pathways involved in p53-mediated tumor suppression. Carcinogenesis 35:740-6
Wang, Shang-Jui; Gu, Wei (2014) To be, or not to be: functional dilemma of p53 metabolic regulation. Curr Opin Oncol 26:78-85
Smith, Steven G; Sanchez, Roberto; Zhou, Ming-Ming (2014) Privileged diazepine compounds and their emergence as bromodomain inhibitors. Chem Biol 21:573-83
Mungamuri, Sathish Kumar; Murk, William; Grumolato, Luca et al. (2013) Chromatin modifications sequentially enhance ErbB2 expression in ErbB2-positive breast cancers. Cell Rep 5:302-13
Kracikova, M; Akiri, G; George, A et al. (2013) A threshold mechanism mediates p53 cell fate decision between growth arrest and apoptosis. Cell Death Differ 20:576-88
Senturk, Emir; Manfredi, James J (2013) p53 and cell cycle effects after DNA damage. Methods Mol Biol 962:49-61
Hamard, Pierre-Jacques; Barthelery, Nicolas; Hogstad, Brandon et al. (2013) The C terminus of p53 regulates gene expression by multiple mechanisms in a target- and tissue-specific manner in vivo. Genes Dev 27:1868-85
Chen, Delin; Kon, Ning; Zhong, Jiayun et al. (2013) Differential effects on ARF stability by normal versus oncogenic levels of c-Myc expression. Mol Cell 51:46-56
Namba, Takushi; Tian, Fang; Chu, Kiki et al. (2013) CDIP1-BAP31 complex transduces apoptotic signals from endoplasmic reticulum to mitochondria under endoplasmic reticulum stress. Cell Rep 5:331-9

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