Studies on Nuclear Receptors Nor1 and NGFI-B/Nur77

PABLO M FERNANDEZ; CARLOS F AGUILAR; MARIO M. ZAKIN

Mendoza

Workshop; 3rd International Workshop Molecular Biology of Stress Responses; 2001

Studies in Nur-77 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 Nur-77-related orphan receptors may substitute Nur77 functions in the hypothalamo-pituitary-adrenal axis by a compensatory mechanism. We demonstrate that Nor1, the most recently cloned member of the NGFI-B/Nur77 subfamily, is expressed in the pituitary gland and adrenal cortex, and that ACTH and Angiotensin II (AngII) treatment of adrenal fasciculate cells induces Nor1 expression. The results strongly suggest that Nor1 is an intermediate in the long term consequences of ACTH or AngII treatment. The overall structural and functional organization of Nor1 and NGFI-B/Nur77 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, Nor1 is not an efficient substitute for the NGFI-B/Nur77 activation of the POMC gene expression in pituitary glands. The 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. Serine/treonine kinases and phosphatases have been involved in the control of the NGFI-B/Nur77 nuclear receptor subfamily during ACTH treatment of adrenal cells. In further experiments, we analyse the potential role of the serine/threonine Protein Phosphatase 2A (PP2A) in NGFI-B/Nur77 transcription. The results strongly suggest that PP2A regulates in vivo NGFI-B/Nur77 gene transcription.