STAT3-protein interactions in IL-6/gp130 signaling

dc.contributor.advisorJohn Papaconstantinouen_US
dc.contributor.committeeMemberkishor bhakaten_US
dc.contributor.committeeMemberJohn DiGiovannien_US
dc.contributor.committeeMemberIstvan Boldoghen_US
dc.contributor.committeeMemberchunming Liuen_US
dc.contributor.committeeMemberAllan Brasieren_US
dc.creatorTIEYING HOUen_US
dc.description.abstractThe 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 (ã-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.en_US
dc.rightsCopyright © is held by the author. Presentation of this material on the TDL web site by The University of Texas Medical Branch at Galveston was made possible under a limited license grant from the author who has retained all copyrights in the works.en_US
dc.titleSTAT3-protein interactions in IL-6/gp130 signalingen_US
dc.type.materialtexten_US and Molecular Biologyen_US University of Texas Medical Branchen_US


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