): In response to interferon, growth hormone, erythropoeitin, epidermal growth factor and over 50 other extracellular signaling proteins, the STATs (signal transducers and activators of transcription) become activated, accumulate in the nucleus, bind DNA and participate in regulating gene expression. A great many decisive physiologic events during development and in adulthood depend upon these signaling pathways. For example, Stati is not only required in the first line of host defense against bacterial and viral infection but also in growth restraint. In contrast, Stat3 has recently been implicated in preventing apoptosis in human cancers and a constitutively active Stat3 (Stat3-C) has been found to be able to transform cultured cells into cancer cells. Understanding the biochemical details of how Stat3 in cooperation with other specific nuclear proteins in structures called enhanceosomes governs gene expression is a major goal of this research. We will explore and further expand current knowledge of how Stat3 interacts with itself as a tetramer, with c-Jun, with the glucocorticoid receptor and with an HMG-box protein to effect immediately increased transcription. We will extend previous crystallographic structure studies to include Stat:c-Jun complexes. The genes that Stat3 and Stat3-C activate in transformed cells and the specific residues required for transformation within known structural domains of Stat3 will be determined. Cell-based transformation assays, protein:protein association assays, crystallographic analysis of appropriate pairwise interactions, in .vivo and in vitro transcription analysis and mouse genetics of Stat3 mutants will all be used in these studies. The detailed knowledge of Stat3 as a transcriptional activator and its role in cell transformation, will greatly aid in the discovery of drugs that inhibit persistently active Stat3 and possibly inhibit cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI032489-11
Application #
6332127
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Laughlin, Catherine A
Project Start
1991-08-01
Project End
2006-04-30
Budget Start
2001-06-01
Budget End
2002-04-30
Support Year
11
Fiscal Year
2001
Total Cost
$459,325
Indirect Cost
Name
Rockefeller University
Department
Anatomy/Cell Biology
Type
Other Domestic Higher Education
DUNS #
071037113
City
New York
State
NY
Country
United States
Zip Code
10065
Ahmed, Simi T; Darnell Jr, James E (2009) Serpin B3/B4, activated by STAT3, promote survival of squamous carcinoma cells. Biochem Biophys Res Commun 378:821-5
Betz, Aurel; Ryoo, Hyung Don; Steller, Hermann et al. (2008) STAT92E is a positive regulator of Drosophila inhibitor of apoptosis 1 (DIAP/1) and protects against radiation-induced apoptosis. Proc Natl Acad Sci U S A 105:13805-10
Ginsberg, Michael; Czeko, Elmar; Muller, Patrick et al. (2007) Amino acid residues required for physical and cooperative transcriptional interaction of STAT3 and AP-1 proteins c-Jun and c-Fos. Mol Cell Biol 27:6300-8
Mertens, Claudia; Zhong, Minghao; Krishnaraj, Ravi et al. (2006) Dephosphorylation of phosphotyrosine on STAT1 dimers requires extensive spatial reorientation of the monomers facilitated by the N-terminal domain. Genes Dev 20:3372-81
Shen, Yuhong; La Perle, Krista M D; Levy, David E et al. (2005) Reduced STAT3 activity in mice mimics clinical disease syndromes. Biochem Biophys Res Commun 330:305-9
Paz, Keren; Socci, Nicholas D; van Nimwegen, Erik et al. (2004) Transformation fingerprint: induced STAT3-C, v-Src and Ha-Ras cause small initial changes but similar established profiles in mRNA. Oncogene 23:8455-63
Shen, Yuhong; Schlessinger, Karni; Zhu, Xuejun et al. (2004) Essential role of STAT3 in postnatal survival and growth revealed by mice lacking STAT3 serine 727 phosphorylation. Mol Cell Biol 24:407-19
Yang, Edward; Lerner, Lorena; Besser, Daniel et al. (2003) Independent and cooperative activation of chromosomal c-fos promoter by STAT3. J Biol Chem 278:15794-9
Yang, Edward; van Nimwegen, Erik; Zavolan, Mihaela et al. (2003) Decay rates of human mRNAs: correlation with functional characteristics and sequence attributes. Genome Res 13:1863-72
Lerner, Lorena; Henriksen, Melissa A; Zhang, Xiaokui et al. (2003) STAT3-dependent enhanceosome assembly and disassembly: synergy with GR for full transcriptional increase of the alpha 2-macroglobulin gene. Genes Dev 17:2564-77

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