Rapid advances in the characterization of eukaryotic genomes have led to an awareness of the increasing complexity in cellular growth controls and the mechanisms by which their deregulation contributes to cancer. Signaling pathways are interconnected through multiple effectors that determine cell fate. The tumor suppressor gene p53 is one such critical effector. Loss of p53 function is found in most human cancers and can be an early or late event in the malignant process. Accumulating evidence indicates that p53 is induced by and plays a major role in determining cellular responses to a variety of pathophysiologic stresses. p53 functions importantly in determining cell fate decisions including growth arrest, replicative senescence or apoptotic cell death. The Program goals are to elucidate mechanisms involved in p53 regulation and functions from novel perspectives of discoveries made within the Program and to elucidate signaling pathways critical to cellular stress responses. Recent discoveries within the Program have demonstrated that p53 contributes to innate immunity by enhancing Interferon and TNFa signaling pathways through novel p53 target genes. The overall long term objectives of this research are to develop understanding of mechanisms by which p53 integrates responses to cellular stresses at the transcriptional level in innate immunity that may act to suppress tumor development through cross talk within the tumor microenvironment. The functions of p53 in innate antiviral immunity will be further explored as well. Other projects are exploiting research advances in investigations of p53 posttranslational modifications on p53's ability to regulate and integrate transcriptional responses that determine cell fate decisions utilizing an array of complementary approaches including molecular and cell biology, structural and chemical biology. This Program brings together a senior group of investigators from different disciplines and with complementary expertise focused on important and novel aspects of p53 biology.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA080058-13
Application #
8288898
Study Section
Special Emphasis Panel (ZCA1-GRB-S (J1))
Program Officer
Watson, Joanna M
Project Start
2000-02-16
Project End
2015-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
13
Fiscal Year
2012
Total Cost
$1,419,497
Indirect Cost
$389,021
Name
Icahn School of Medicine at Mount Sinai
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Mungamuri, S K; Wang, S; Manfredi, J J et al. (2015) Ash2L enables P53-dependent apoptosis by favoring stable transcription pre-initiation complex formation on its pro-apoptotic target promoters. Oncogene 34:2461-70
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

Showing the most recent 10 out of 40 publications