Cytokines and growth factors play important roles in regulating cell growth, differentiation and function. The JAK-STAT signaling pathway is the major pathway for transducing signals from a multitude of cytokines and growth factors directly into the nucleus, regulating a diverse array of biological functions including immune response, cellular development, and oncogenesis. The STAT proteins (Signal Transducer and Activator of Transcription) become phosphorylated, dimerize, enter the nucleus and bind to specific DNA sequences to activate transcription. Much analysis has been focused on the transduction of signals by the STAT proteins, while little is known about their mode of stimulating transcription of an otherwise silent gene. To further understand the JAK-STAT pathway, particularly signaling into the nucleus and mechanism of transcription activation by STATs, it is essential to identify the protein players that are brought together by STATs in the process of transcription activation. We will use Stat1 and the IFN-gamma signaling pathway as a model system to test the hypothesis that STAT proteins recruit a set of co-activators, some of which maybe unique to STATs, to regulate gene expression in response to cytokines and growth factors. The central goal of this proposal is to identify the transcription co-activators interacting with Stat1 using affinity-purification and mass spectrometry techniques. The structural and functional importance of these co-activators will be analyzed using biochemical and molecular approaches. Identification of these proteins involved in the process of transcription activation by Stat1 will not only provide insight into the IFN-gamma signaling pathway and other cytokine signaling pathways involving different STATs, but also contribute to the understanding of the general mechanism of transcription activation.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Cell Development and Function Integrated Review Group (CDF)
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Anderson, Richard A
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Weill Medical College of Cornell University
Schools of Medicine
New York
United States
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Snyder, Marylynn; Huang, Xin-Yun; Zhang, J Jillian (2009) The minichromosome maintenance proteins 2-7 (MCM2-7) are necessary for RNA polymerase II (Pol II)-mediated transcription. J Biol Chem 284:13466-72
Sun, Wei; Snyder, Marylynn; Levy, David E et al. (2006) Regulation of Stat3 transcriptional activity by the conserved LPMSP motif for OSM and IL-6 signaling. FEBS Lett 580:5880-4
Snyder, Marylynn; He, Wei; Zhang, J Jillian (2005) The DNA replication factor MCM5 is essential for Stat1-mediated transcriptional activation. Proc Natl Acad Sci U S A 102:14539-44
Xu, Weifeng; Zhang, J Jillian (2005) Stat1-dependent synergistic activation of T-bet for IgG2a production during early stage of B cell activation. J Immunol 175:7419-24
Xu, Weifeng; Nair, Jayasree S; Malhotra, Ajay et al. (2005) B cell antigen receptor signaling enhances IFN-gamma-induced Stat1 target gene expression through calcium mobilization and activation of multiple serine kinase pathways. J Interferon Cytokine Res 25:113-24
Sun, Wei; Xu, Weifeng; Snyder, Marylynn et al. (2005) The conserved Leu-724 residue is required for both serine phosphorylation and co-activator recruitment for Stat1-mediated transcription activation in response to interferon-gamma. J Biol Chem 280:41844-51
Nair, Jayasree S; DaFonseca, Christopher J; Tjernberg, Agneta et al. (2002) Requirement of Ca2+ and CaMKII for Stat1 Ser-727 phosphorylation in response to IFN-gamma. Proc Natl Acad Sci U S A 99:5971-6
DaFonseca, C J; Shu, F; Zhang, J J (2001) Identification of two residues in MCM5 critical for the assembly of MCM complexes and Stat1-mediated transcription activation in response to IFN-gamma. Proc Natl Acad Sci U S A 98:3034-9