The functional role of an interleukin 6-inducible CDK9•STAT3 complex in human γ-fibrinogen gene expression
The functional role of an interleukin 6-inducible CDK9•STAT3 complex in human γ-fibrinogen gene expression
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DOI：
10.1074/jbc.m706458200
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发表时间：
2007-12-21
影响因子：
4.8
通讯作者：
Brasier, Allan R.
中科院分区：
文献类型：
--
作者：
Hou, Tieying;Ray, Sutapa;Brasier, Allan R.
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 gamma-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 gamma-FBG expression in HepG2 hepatocarcinoma cells. IL-6 induces rapid nuclear translocation of Tyrphosphorylated 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 gamma-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 gamma-FBG promoter as well as increased loading of RNA Pol II and phospho-Ser(2) CTD Pol II on the TATA box and coding regions. Finally, FP specifically and efficiently inhibits association of phospho-Ser(2) CTD RNA Pol II on the gamma-FBG promoter, indicating that CDK9 kinase activity mediates IL-6-inducible CTD phosphorylation. Our data indicate that IL-6 induces a STAT3 center dot 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.
