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 #
5P01CA080058-12
Application #
8142921
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
2011-07-01
Budget End
2012-06-30
Support Year
12
Fiscal Year
2011
Total Cost
$1,424,298
Indirect Cost
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
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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