Phosphorylation of GATA-4 is involved in alpha 1-adrenergic agonist-responsive transcription of the endothelin-1 gene in cardiac myocytes.

Abstract

The expression of endothelin-1 (ET-1) in cardiac myocytes is markedly induced during the development of heart failure in vivo and by stimulation with the alpha(1)-adrenergic agonist phenylephrine in culture. Although recent studies have suggested a role for cardiac-specific zinc finger GATA factors in the transcriptional pathways that modulate cardiac hypertrophy, it is unknown whether these factors are also involved in cardiac ET-1 transcription and if so, how these factors are modulated during this process. Using transient transfection assays in primary cardiac myocytes from neonatal rats, we show here that the GATA element in the rat ET-1 promoter was required for phenylephrine-stimulated ET-1 transcription. Cardiac GATA-4 bound the ET-1 GATA element and activated the ET-1 promoter in a sequence-specific manner. Stimulation by phenylephrine caused serine phosphorylation of GATA-4 and increased its ability to bind the ET-1 GATA element. Inhibition of the extracellularly responsive kinase cascade with PD098059 blocked the phenylephrine-induced increase in the DNA binding ability and the phosphorylation of GATA-4. These findings demonstrate that serine phosphorylation of GATA-4 is involved in alpha(1)-adrenergic agonist-responsive transcription of the ET-1 gene in cardiac myocytes and that extracellularly responsive kinase 1/2 activation plays a role upstream of GATA-4.

• Authors: T Morimoto, K Hasegawa, S Kaburagi, T Kakita, H Wada, T Yanazume, S Sasayama
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 275 Issue 18 Pg. 13721-6 (May 05 2000) ISSN: 0021-9258 [Print] United States
• PMID: 10788492 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adrenergic alpha-1 Receptor Agonists
• Adrenergic alpha-Agonists
• DNA-Binding Proteins
• Endothelin-1
• GATA4 Transcription Factor
• Receptors, Adrenergic, alpha-1
• Transcription Factors
• Phenylephrine

Topics

• Adrenergic alpha-1 Receptor Agonists
• Adrenergic alpha-Agonists (pharmacology)
• Animals
• DNA-Binding Proteins (genetics, metabolism)
• Endothelin-1 (genetics, metabolism)
• GATA4 Transcription Factor
• Gene Expression Regulation
• Phenylephrine (pharmacology)
• Phosphorylation
• Rats
• Rats, Sprague-Dawley
• Receptors, Adrenergic, alpha-1 (genetics, metabolism)
• Signal Transduction (drug effects)
• Transcription Factors (genetics, metabolism)
• Transcription, Genetic