The STAT proteins are latent cytoplasmic transcription factors that are activated by tyrosine phosphorylation through cytokine and growth factor interaction with their specific cell surface receptors. STATS regulate many genes that are crucial to innate immunity (mediated through STATs 1 and 2 and interferons), adaptive immunity (mediated by IL-12, IL-4 through STATs 4 and 6 and a host of other cytokines) as well as growth, development and differentiation (mediated through dozens of receptor tyrosine kinases activating particularly STATS). Not only the activation but the regulated inactivation of the STATs are vital to proper functioning since over-activity particularly of STAT3 in cancer is widespread. Drawing on new structural and cellular biochemical data we have proposed a new model of inactivation. This process of dephosphorylation appears to require intra-protein contacts and extensive mutagenesis of the known and proposed contact interfaces in both STAT1 and STAT4 is described to study both in vitro and in vivo interactions and resulting effects of such interactions. In many human cancers STAT3 is persistently activated not due to STAT3 mutations but to overactivity of kinases that activate STAT3 or loss of negative acting proteins, leading to a resistance to apoptosis. We believe that the best way to intervene in STATS dependent cancer cells is direct inhibition of STATS in the act of stimulating transcription. To this end we study the interaction of STATS with other nuclear proteins whose interactions are required for STATS dependent transcription. We have found and will continue to study a STATS/cJun/cFos interaction on a model enhanceosome and extend these studies to genes (e.g. Bcl-xL) that establish an anti-apoptotic shield in the presence of persistently active STATS. Details of persistently active STATS in anti-apoptosis will be studied by abruptly removing active STATS by treatment of cells with anti IL-6 antibodies and then determining the balance of mRNAs and proteins related to apoptosis. From the studies of STAT1 dephosphorylation and of STATS protein contacts will come discreet targets for development of small molecule inhibitors. Inhibition of dephosphorylation of STAT1 would prolong interferon action;inhibition of STATS activity would induce apoptosis in cancer cells. These basic studies coupled with drug discovery programs, for example in industry, should definitely lead to new drugs in the treatment of cancer and of viral infections.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI032489-20
Application #
7810554
Study Section
Special Emphasis Panel (ZRG1-CSD-D (01))
Program Officer
Cassetti, Cristina
Project Start
1991-08-01
Project End
2012-04-30
Budget Start
2010-05-01
Budget End
2012-04-30
Support Year
20
Fiscal Year
2010
Total Cost
$398,429
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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