A mechanistic basis for distinct mineralocorticoid and glucocorticoid receptor transcriptional specificities

The mineralocorticoid and glucocorticoid receptors (MR and GR, respectively) are closely related members of the nuclear receptor superfamily. Despite marked functional similarities and a high degree of sequence conservation between MR and GR, the mineralocorticoid and glucocorticoid hormones elicit markedly different physiological effects, even in cells expressing both receptors. Hormone specificity is, in part, determined by the actions of 11 beta-hydroxysteroid dehydrogenase. However, other mechanisms must obtain in cells that express both receptors and respond differentially to the two classes of hormone. Indeed, MR and GR, while functionally redundant in some contexts, in others display distinct transcriptional specificities. In particular, in the presence of members of the AP1 family of regulatory factors, cJun and cFos, a composite response element, plfG, is GR-specific. Transcription from a plfG-linked gene is stimulated by GR in the presence of cJun and repressed by GR in the presence of cJun and cFos. MR neither stimulates nor represses transcription in the same contexts, thus indicating that receptor transcriptional specificities can be distinguished by differential interactions with nonreceptor factors at a composite response element. The implications of these findings for mineralocorticoid and glucocorticoid hormone specificity in various tissues are discussed.