Signal Transducers and Activators of Transcription (STAT) proteins were originally characterized as latent transcription factors activated by signal-dependent tyrosine phosphorylation. Two founding members of this family, STAT1 and STATS, interact genetically and biochemically and have been shown to function in innate immune and inflammatory responses. Recent evidence also shows that STAT1 has characteristics of a tumor suppressor and STAT3 has characteristics of an oncogene, and these proteins play important but as yet poorly understood roles in cancer progression. A large body of research has fleshed out details of the JAK-STAT pathway, demonstrating the importance of tyrosine phosphorylation, dimerization, nuclear translocation, DMA binding, and transcription induction, features that fit the originally postulated role of STAT proteins as direct transducers of extracellular signals. While this paradigm has served to explain many aspects of STAT function, emerging data suggest that some biological functions of STAT1 and 3 are independent of one or more of the cornerstones of the canonical pathway.We proopse to explore the molecular mechanisms and biological consequences of STAT-dependent processes that are not fully explained by current models of JAK-STAT signaling. We propose to pursue the following specific aims: 1. Characterize the essential role of STATS in trophectoderm function and embryonic development. 2. Characterize the role of STATS in Ras-induced cancer. 3. Characterize the regulation, interaction, and function of STAT1 and STATS during the cell cycle. This research will be facilitated by our extensive collection of genetic and biochemical resources, including single and double mutant cells and animals, tissue-specific mutant animals, animal models of cancer, and antibody and molecular tools specific for STAT proteins. Achievement of the goals of this proposal will increase our understanding of the complex roles of these proteins in normal biology and cancer, will bridge a major gap in our current understanding of the mechanisms of STAT function, will further our efforts towards optimization of therapeutic strategies targeting STATS,and will facilitate development of novel strategies for better diagnosis and treatment of human disease.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZRG1-CSD-D (01))
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Mallia, Conrad M
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New York University
Schools of Medicine
New York
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Genini, Davide; Brambilla, Lara; Laurini, Erik et al. (2017) Mitochondrial dysfunction induced by a SH2 domain-targeting STAT3 inhibitor leads to metabolic synthetic lethality in cancer cells. Proc Natl Acad Sci U S A 114:E4924-E4933
Garama, Daniel J; Harris, Tiffany J; White, Christine L et al. (2015) A Synthetic Lethal Interaction between Glutathione Synthesis and Mitochondrial Reactive Oxygen Species Provides a Tumor-Specific Vulnerability Dependent on STAT3. Mol Cell Biol 35:3646-56
Gough, Daniel J; MariƩ, Isabelle J; Lobry, Camille et al. (2014) STAT3 supports experimental K-RasG12D-induced murine myeloproliferative neoplasms dependent on serine phosphorylation. Blood 124:2252-61
Gnatovskiy, Leonid; Mita, Paolo; Levy, David E (2013) The human RVB complex is required for efficient transcription of type I interferon-stimulated genes. Mol Cell Biol 33:3817-25
Gough, Daniel J; Koetz, Lisa; Levy, David E (2013) The MEK-ERK pathway is necessary for serine phosphorylation of mitochondrial STAT3 and Ras-mediated transformation. PLoS One 8:e83395
Gough, Daniel J; Messina, Nicole L; Clarke, Christopher J P et al. (2012) Constitutive type I interferon modulates homeostatic balance through tonic signaling. Immunity 36:166-74
Levy, David E; MariƩ, Isabelle J (2012) STATus report on tetramers. Immunity 36:553-5
Lee, Jason E; Yang, Yang-Ming; Liang, Feng-Xia et al. (2012) Nongenomic STAT5-dependent effects on Golgi apparatus and endoplasmic reticulum structure and function. Am J Physiol Cell Physiol 302:C804-20
Zhang, Liang; Das, Priyabrata; Schmolke, Mirco et al. (2012) Inhibition of pyrimidine synthesis reverses viral virulence factor-mediated block of mRNA nuclear export. J Cell Biol 196:315-26
O'Brien, Meagan; Manches, Olivier; Sabado, Rachel Lubong et al. (2011) Spatiotemporal trafficking of HIV in human plasmacytoid dendritic cells defines a persistently IFN-*-producing and partially matured phenotype. J Clin Invest 121:1088-101

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