Angiotensinogen gene expression is dependent on signal transducer and activator of transcription 3-mediated p300/cAMP response element binding protein-binding protein coactivator recruitment and histone acetyltransferase activity.
Angiotensin II, a potent vasoactive peptide produced by proteolysis of the angiotensinogen (AGT) prohormone, plays a critical role in cardiovascular homeostasis. Recently we showed that IL-6 induces human (h)AGT transcription by activating the signal transducers and activators of transcription (STATs). Here we investigated the role of the coactivator p300/cAMP response ... element binding protein-binding protein (CBP) in STAT3-mediated hAGT gene expression. Overexpression of adenovirus 12S E1A, which binds and inactivates p300/CBP, strongly inhibited basal and stimulated hAGT transcription, whereas a mutant E1A defective in binding p300/CBP did not. Conversely, ectopic expression of p300 and CBP potentiated inducible hAGT promoter activity. Coimmunoprecipitation assays revealed STAT3-p300 interaction upon IL-6 stimulation. The STAT3-p300 association requires the STAT3 C-terminal transactivation domain, as STAT3 deleted of transactivation functions as a dominant-negative inhibitor and does not associate with p300/CBP. The observation that IL-6 stimulation increases histone H4 acetylation of the endogenous hAGT promoter, and expression of p300 deficient in histone acetyltransferase activity down-regulates hAGT promoter activity both suggest that p300 histone acetyltransferase activity is required for hAGT expression. Finally, treatment of HepG2 cells with a histone deacetylase inhibitor increased the hAGT mRNA abundance by 2- to 3-fold. Taken together, our results indicate that IL-6-inducible expression of the hAGT promoter is mediated by physical association of the COOH terminus of STAT3 with p300/CBP, the recruitment of which targets histone acetylation and results in chromatin remodeling.
Mesh Terms:
Acetyltransferases, Adenovirus E1A Proteins, Angiotensinogen, CREB-Binding Protein, Cell Line, DNA-Binding Proteins, Gene Expression Regulation, Histone Acetyltransferases, Histone Deacetylase Inhibitors, Histones, Humans, Interleukin-6, Nuclear Proteins, Promoter Regions, Genetic, RNA, Messenger, STAT3 Transcription Factor, Saccharomyces cerevisiae Proteins, Trans-Activators
Acetyltransferases, Adenovirus E1A Proteins, Angiotensinogen, CREB-Binding Protein, Cell Line, DNA-Binding Proteins, Gene Expression Regulation, Histone Acetyltransferases, Histone Deacetylase Inhibitors, Histones, Humans, Interleukin-6, Nuclear Proteins, Promoter Regions, Genetic, RNA, Messenger, STAT3 Transcription Factor, Saccharomyces cerevisiae Proteins, Trans-Activators
Mol. Endocrinol.
Date: Apr. 01, 2002
PubMed ID: 11923478
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