The N-terminal domain of the mineralocorticoid receptor modulates both mineralocorticoid receptor- and glucocorticoid receptor-mediated transactivation from Na/K ATPase beta1 target gene promoter.
Mineralocorticoid and glucocorticoid hormones activate the expression of the Na/K ATPase beta1 through direct binding of the mineralocorticoid receptor (MR) and glucocorticoid receptors (GR) to a mineralocorticoid- and glucocorticoid-responsive element in the beta1 promoter region, but activation of the beta1 promoter is inhibited by coexpression of both receptors. Here, using a series of mutated and chimeric receptors, we show that the N-terminal region of MR mediates an inhibitory effect on MR and GR activation from the beta1 promoter, in CV-1 cells. Deletion of the N-terminal region of MR (1-603) enhanced MR activation four-fold. Activation by chimeric MR, in which the N-terminus of GR replaces the N-terminal region of MR, was threefold that of wild-type MR. In addition, whereas coexpression of wild-type MR and GR was inhibitory, coexpression of chimeric MR and wild-type GR was nearly equal to that of MR. By contrast, mutated GR lacking its N-terminal region (1-420) was less efficient than the wild type in activating this promoter. These results demonstrate that the N-terminal domains of MR and GR have opposite transactivation properties and that MR region 1-603 is indeed inhibitory for both MR- and GR-mediated regulation of the Na/K ATPase beta1 gene promoter.
Derfoul
A
A
Department of Biochemistry and Molecular Pharmacology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Robertson
N M
NM
Hall
D J
DJ
Litwack
G
G
D002460:Cell Line; D004247:DNA / Q000378:metabolism; D019281:Dimerization; D017353:Gene Deletion; D015870:Gene Expression; D006801:Humans; D008156:Luciferases / Q000235:genetics; D016296:Mutagenesis; D010446:Peptide Fragments / Q000737:chemistry / Q000502:physiology*; D011401:Promoter Regions, Genetic; D011965:Receptors, Glucocorticoid / Q000502:physiology*; D018161:Receptors, Mineralocorticoid / Q000737:chemistry* / Q000502:physiology*; D011993:Recombinant Fusion Proteins; D020218:Response Elements; D000254:Sodium-Potassium-Exchanging ATPase / Q000235:genetics*; D013329:Structure-Activity Relationship; D015533:Transcriptional Activation; D014162:Transfection
D010446:Peptide Fragments; D011965:Receptors, Glucocorticoid; D018161:Receptors, Mineralocorticoid; D011993:Recombinant Fusion Proteins; D004247:DNA; D008156:Luciferases; D000254:Sodium-Potassium-Exchanging ATPase