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J. Biol. Chem., Vol. 282, Issue 51, 37091-37102, December 21, 2007

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The Functional Role of an Interleukin 6-inducible CDK9·STAT3 Complex in Human -Fibrinogen Gene Expression^*

Tieying Hou, Sutapa Ray, and Allan R. Brasier^¶1

From the Departments of Biochemistry and Molecular Biology, Internal Medicine, and ^¶Sealy Center for Molecular Medicine, University of Texas Medical Branch, Galveston, Texas 77555-1060

The signal transducer and activator of transcription 3 (STAT3) is an IL-6-inducible transcription factor that mediates the hepatic acute phase response (APR). Using -fibrinogen (FBG) as a model of the APR, we investigated the requirement of an IL-6-inducible complex of STAT3 with cyclin-dependent kinase 9 (CDK9) on -FBG expression in HepG2 hepatocarcinoma cells. IL-6 induces rapid nuclear translocation of Tyr-phosphorylated STAT3 that forms a nuclear complex with CDK9 in nondenaturing co-immunoprecipitation and confocal colocalization assays. To further understand this interaction, we found that CDK9-STAT3 binding is mediated via both STAT NH₂-terminal modulatory and COOH-terminal transactivation domains. Both IL-6-inducible -FBG reporter gene and endogenous mRNA expression are significantly decreased after CDK9 inhibition using the potent CDK inhibitor, flavopiridol (FP), or specific CDK9 siRNA. Moreover, chromatin immunoprecipitation (ChIP) experiments revealed an IL-6-inducible STAT3 and CDK9 binding to the proximal -FBG promoter as well as increased loading of RNA Pol II and phospho-Ser² CTD Pol II on the TATA box and coding regions. Finally, FP specifically and efficiently inhibits association of phospho-Ser² CTD RNA Pol II on the -FBG promoter, indicating that CDK9 kinase activity mediates IL-6-inducible CTD phosphorylation. Our data indicate that IL-6 induces a STAT3·CDK9 complex mediated by bivalent STAT3 domains and CDK9 kinase activity is necessary for licensing Pol II to enter a transcriptional elongation mode. Therefore, disruption of IL-6 signaling by CDK9 inhibitors could be a potential therapeutic strategy for inflammatory disease.

Received for publication, August 3, 2007 , and in revised form, October 22, 2007.

^* This work was supported by NHLBI, National Institutes of Health Grant R01 HL070925 (to A. R. B.). Core Laboratory support was from NIEHS, National Institutes of Health Grant P30 ES06676 (to J. H., UTMB). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Division of Endocrinology, MRB 8.138, University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555-1060. Tel.: 409-772-2824; Fax: 409-772-8709; E-mail: arbrasie{at}utmb.edu.

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