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

Studies in Nur77-deficient mice have shown that the basal regulation of hyp othalamic and pituitary functions as well as the adrenocortical steroidogen esis in these animals is normal. This indicates that Nur77-related orphan r eceptors may substitute Nur77 functions in the hypothalamo-pituitary-adrena l axis by a compensatory mechanism. Nor1 is the most recently cloned member of the NGFI-B/Nur77 subfamily, and its properties are still largely unknow n. We demonstrate here that Norl is expressed in the pituitary gland and ad renal 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 adre nal cells strongly suggest that Nor1 is an intermediate in the long-term co nsequences of ACTH or AngII treatment. The Nor1 and NGFI-B/Nur77 amino acid sequence homology and the analysis of the traits-activation properties of Nor1 show that the overall structural and functional organization of the tw o proteins is similar. As observed with NGFI-B/Nur77, Norl activates the ex pression of genes encoding steroidogenic enzymes as P450c21, through its in teraction with NGFI-B response element promoter sequences. In contrast, bin ding experiments of Nor1 with the palindromic NurRE sequence suggest that N or1 is not an efficient substitute for the NGFI-B/Nur77 activation of the P OMC gene expression in pituitary glands. All these results indicate that No r1 and NGFI-B/Nur77 may play similar albeit distinct rules in the hypothala mo-pituitary-adrenal axis. Further experiments also show that the mechanism s responsible for the transcriptional regulation of Nor1 in adrenal cells a ppear to depend on the protein kinase A and protein kinase C cascades.