Different polypeptide ligands can bind to specific cell surface receptors on the same cell and initiate different intracellular events including the immediate (non-protein synthesis requiring) activation of different sets of genes. We have discovered latent cytoplasmic transcription factors that are activated by such ligands. Those latent cytoplasmic proteins, termed STAT proteins for signal transducers and activators of transcription are phosphorylated on tyrosine in the cytoplasm before translocating to the nucleus to direct transcription. They were first discovered in cells treated with IFN-alpha or IFN-gamma. In this proposal we describe experiments to define the functional domains of one of these proteins, STAT 91, and the functional domains of the kinases (Jak1 and Jak2) that have been shown to be involved in the STAT activation pathway. A most important thrust of future work will be discover other proteins in this same family that serve in response to other ligands. Because the genes encoding the presently known STAT proteins have been found to have many (20) exons we will study the STAT mRNAs in different mouse tissues and in cells treated in a variety of ways to search for differently spliced STAT mRNAs that might function in different ligand-dependent pathways. Several newly discovered STAT protein family members with mRNAs that are present in the thymus are also described that have high homology to but are distinctly different from the already described STAT 91 and 113 proteins. Characterization of these proteins with particular attention to their possible tyrosine phosphorylation in response to other ligands is an important part of this proposal. Finally, collaboration is planned to study the three- dimensional structure of important domains of the STAT proteins and the kinases with which they interact.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI034420-05
Application #
2653832
Study Section
Molecular Biology Study Section (MBY)
Project Start
1994-05-01
Project End
1999-01-31
Budget Start
1998-02-01
Budget End
1999-01-31
Support Year
5
Fiscal Year
1998
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
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
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

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