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
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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
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Hiraki, Masatsugu; Hwang, So-Young; Cao, Shugeng et al. (2015) Small-Molecule Reactivation of Mutant p53 to Wild-Type-like p53 through the p53-Hsp40 Regulatory Axis. Chem Biol 22:1206-16
Resnick-Silverman, Lois; Manfredi, James J (2015) Two Faces of SIVA. Cancer Discov 5:581-3
Jiang, Le; Kon, Ning; Li, Tongyuan et al. (2015) Ferroptosis as a p53-mediated activity during tumour suppression. Nature 520:57-62

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