Evidence for the regulation of Na+, K(+)-ATPase alpha 1 gene expression through the interaction of aldosterone and cAMP-inducible transcriptional factors.
Mineralocorticoid hormones such as aldosterone modulate cellular ion homeostasis at least in part through the regulation of Na+, K(+)-ATPase (NAKA) gene expression. While aldosterone acts at the transcriptional level through its ligand-inducible mineralocorticoid receptor (MR), tissue specific and other transcriptional factors may interact with the MR to modulate this regulatory response. cAMP also regulates NAKA alpha 1 gene expression which at the transcriptional level is mediated, in part, through a cAMP response element (CRE) present on a highly conserved, 48 base pair enhancer region, the PUC-1 core, of the rat NAKA alpha 1 subunit gene promoter. We have tested the hypothesis that the MR interacts with cAMP induced transcriptional factors to modulate the NAKA alpha 1 gene expression. In transient transfection studies a PUC-1 core attached to an enhancerless SV40 promoter driven reporter gene (pB1CAT) was induced by 8-bromo-cAMP in HeLa cells. Co-transfected MR expression vector inhibited the 8-bromo-cAMP inducible activity of pB1CAT. DNA binding studies suggested that the PUC-1 core binds both CREB/ATF proteins as well as the glucocorticoid hormone class of steroid receptors. These results suggest that the MR suppresses cAMP-mediated activation of PUC-1 core driven CAT activity possibly through a direct interaction with CREB/ATF transcriptional factors. This in turn suggests that the interaction of two distinct signal transduction systems, aldosterone and cAMP, may define the mineralocorticoid responsiveness of the Na+, K(+)-ATPase alpha 1 gene.
Ahmad
M
M
Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
Medford
R M
RM
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology*; D051698:Activating Transcription Factor 2; D000450:Aldosterone / Q000494:pharmacology*; D001483:Base Sequence; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D008969:Molecular Sequence Data; D018161:Receptors, Mineralocorticoid / Q000096:biosynthesis; D000254:Sodium-Potassium-Exchanging ATPase / Q000235:genetics*; D014157:Transcription Factors / Q000096:biosynthesis*; D015533:Transcriptional Activation
D051698:Activating Transcription Factor 2; D017362:Cyclic AMP Response Element-Binding Protein; D018161:Receptors, Mineralocorticoid; D014157:Transcription Factors; D015124:8-Bromo Cyclic Adenosine Monophosphate; D000450:Aldosterone; D000254:Sodium-Potassium-Exchanging ATPase