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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
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Special Emphasis Panel (ZCA1-GRB-S (J1))
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Watson, Joanna M
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Icahn School of Medicine at Mount Sinai
Internal Medicine/Medicine
Schools of Medicine
New York
United States
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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
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