STAT3-protein interactions in IL-6/gp130 signaling

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Title: STAT3-protein interactions in IL-6/gp130 signaling
Abstract: The Signal Transducer and Activator of Transcription 3 (STAT3 ) is a central transcription factor downstream of IL -6 /gp130 signaling . This thesis investigates how STAT3 regulates IL -6 signal transduction by interacting with its coactivators . First , the function of an IL -6 inducible complex of STAT3 with cyclin -dependent kinase 9 (CDK9 ) was examined by using gamma -Fibrinogen -FBG ) , an acute phase protein , as a model . IL -6 induces a strong nuclear association of STAT3 with CDK9 , which is mediated via both STAT’s NH2 -terminal and COOH -terminal domains . The induction of ã -FBG by IL -6 is significantly decreased when CDK9 is repressed by kinase inhibitor or downregulated by siRNA . Moreover , an IL -6 -inducible STAT3 and CDK9 binding to the proximal ã -FBG promoter is observed . This phenomenon is accompanied by increased loading of RNA Pol II and phospho -Ser2 CTD Pol II on the ã -FBG TATA box and coding regions . Finally , both IL -6 -inducible RNA Pol II and phospho -S2 CTD RNA Pol II association with the endogenous ã -FBG gene are significantly decreased when CDK9 kinase activity is inhibited . In this study we provide evidence that activated STAT3 regulates the transcription elongation of the ã -FBG gene by associating with CDK9 . The magnitude of IL -6 /gp130 signaling is also regulated by p300 , another coactivator of STAT3 with histone acetyltransferase activity (HAT ) . The p300 -STAT3 interaction is partially regulated by the STAT3 NH2 -terminal domain . The second part of this thesis investigates the STAT3 NH2 -terminal function and how its interaction with p300 regulates STAT3 signal transduction . The STAT3 NH2 -terminal domain is required for the downstream gene expression , including socs3 , c -fos and p21 . Additionally , the recruitment of p300 and RNA Pol II to the socs3 promoter is reduced in MEFs stably expressing STAT3 -DN mutant which is deficient in the NH2 -terminal domain . We also reported that the binding site of the STAT3 NH2 -terminal domain maps to the p300 bromodomain and the STAT3 NH2 -terminal acetylation induced by p300 stabilizes this interaction . Finally , the deletion of p300 bromodomain not only reduces its binding affinity to STAT3 but also inhibits its association to the socs3 promoter . Our data indicates that the STAT3 NH2 -terminal domain regulates gp130 signaling by interacting with the p300 bromodomain , thereby stabilizing enhanceosome assembly . In summary , my thesis work has described a mechanism by which the STAT3 NH2 -terminal domain controls gene expression by interacting with coactivators and transcriptional elongation factors . The multiple functions of the STAT3 NH2 -terminal domain make it a potential target for the therapeutic modulation in inflammatory disease .
URI: http : / /hdl .handle .net /2152 .3 /218
Date: 2008-08-20


STAT3-protein interactions in IL-6/gp130 signaling. Doctoral dissertation, The University of Texas Medical Branch. Available electronically from http : / /hdl .handle .net /2152 .3 /218 .

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