Many developmental events during embryogenesis and regulatory events in adults depend upon the presence of extracellular signalling polypeptides (ESPs). Over 35 different ESPs exert their immediate effect through the activation of a set of latent transcription factors called STATs, dual function proteins that serve as signal transducers and activators of transcription. The array of physiologic events controlled at least in part by the STATs include innate immunity, i.e. the initial response to invading bacteria and viruses, proper T cell function particularly in choosing the type of immune responses to invading organisms and many other functions in the bone marrow. Developmental events such as proper epithelial cell development in breast tissue and correct responses to growth hormone also depend on these proteins. Finally, proper growth control requires the action of these proteins. This project has the central long-term goal of understanding the molecular basis for the nuclear action of the STATs in changing transcription rates. We will complete our earlier studies on the definition of transcriptional activation domains, TADs, of Stats 1, 2 and 3 by testing in in vivo transcriptional and cell biologic assays the specificity of each TAD. Proteins that are specifically interactive with the -COOH terminal TAD of Stat1, a domain already demonstrated to be required in transcriptional activation have been detected. The identification of each of these TAD-interactive proteins through mass spectrographic identification by peptide content or by cloning genes of previously unrecognized proteins will be a major initial goal. These interactive proteins very likely include co-activators that may be specific for the STAT group of transcription factors. In vivo and in vitro transcriptional assays of the role of these Stat1-TAD interactive proteins will then be carried out. The studies of functional interaction of the Stat 1, 2 and 3 interactive proteins should provide comprehensive insight into how STAT proteins change gene transcription to induce or maintain the specific phenotypic properties associated with the many extracellular signalling polypeptides.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
2R37AI034420-06
Application #
2743544
Study Section
Molecular Cytology Study Section (CTY)
Program Officer
Ridge, John P
Project Start
1994-05-01
Project End
2004-01-31
Budget Start
1999-02-01
Budget End
2000-01-31
Support Year
6
Fiscal Year
1999
Total Cost
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
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
Zakharova, Natalia; Lymar, Elena S; Yang, Edward et al. (2003) Distinct transcriptional activation functions of STAT1alpha and STAT1beta on DNA and chromatin templates. J Biol Chem 278:43067-73
Henriksen, Melissa A; Betz, Aurel; Fuccillo, Marc V et al. (2002) Negative regulation of STAT92E by an N-terminally truncated STAT protein derived from an alternative promoter site. Genes Dev 16:2379-89
Brivanlou, Ali H; Darnell Jr, James E (2002) Signal transduction and the control of gene expression. Science 295:813-8

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