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.
Ray
Sutapa
S
Department of Internal Medicine and Sealy Center for Molecular Sciences, The University of Texas Medical Branch, Galveston, Texas 77555-1060, USA.
Sherman
Christopher T
CT
Lu
Muping
M
Brasier
Allan R
AR
D000123:Acetyltransferases / Q000378:metabolism*; D017500:Adenovirus E1A Proteins / Q000378:metabolism; D000808:Angiotensinogen / Q000235:genetics*; D050882:CREB-Binding Protein; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation; D051548:Histone Acetyltransferases; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology; D009687:Nuclear Proteins / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D050796:STAT3 Transcription Factor; D029701:Saccharomyces cerevisiae Proteins; D015534:Trans-Activators / Q000378:metabolism*
D017500:Adenovirus E1A Proteins; D004268:DNA-Binding Proteins; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D015850:Interleukin-6; D009687:Nuclear Proteins; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D029701:Saccharomyces cerevisiae Proteins; D015534:Trans-Activators; D000808:Angiotensinogen; D000123:Acetyltransferases; D050882:CREB-Binding Protein; C494363:CREBBP protein, human; D051548:Histone Acetyltransferases