Nuclear receptors Nor1 and NGFI-B/Nur77 play similar, albeit distinct, roles in the hypothalamo-pituitary-adrenal axis

Abstract

Studies in Nur77-deficient mice have shown that the basal regulation of hypothalamic and pituitary functions as well as the adrenocortical steroidogenesis in these animals is normal. This indicates that Nur77-related orphan receptors may substitute Nur77 functions in the hypothalamo-pituitary-adrenal axis by a compensatory mechanism. Nor1 is the most recently cloned member of the NGFI-B/Nur77 subfamily, and its properties are still largely unknown. We demonstrate here that Nor1 is expressed in the pituitary gland and adrenal cortex, and that ACTH and angiotensin II (AngII) treatment of adrenal fasciculata cells induces Nor1 expression. Time-course analysis with both hormones on steroidogenic capacity and the specific gene expression in adrenal cells strongly suggest that Nor1 is an intermediate in the long-term consequences of ACTH or AngII treatment. The Nor1 and NGFI-B/Nur77 amino acid sequence homology and the analysis of the trans-activation properties of Nor1 show that the overall structural and functional organization of the two proteins is similar. As observed with NGFI-B/Nur77, Nor1 activates the expression of genes encoding steroidogenic enzymes as P450c21, through its interaction with NGFI-B response element promoter sequences. In contrast, binding experiments of Nor1 with the palindromic NurRE sequence suggest that Nor1 is not an efficient substitute for the NGFI-B/Nur77 activation of the POMC gene expression in pituitary glands. All these results indicate that Nor1 and NGFI-B/Nur77 may play similar albeit distinct roles in the hypothalamo-pituitary-adrenal axis. Further experiments also show that the mechanisms responsible for the transcriptional regulation of Nor1 in adrenal cells appear to depend on the protein kinase A and protein kinase C cascades.