Neuroendocrine regulation of the hypothalamic pituitary adrenal axis by the nurr1/nur77 subfamily of nuclear receptors.
The present study was designed to examine the role of the nurr1/nur77 subfamily of nuclear receptor transcription factors in the regulation of the hypothalamic/pituitary/adrenal axis at the neuroendocrine level. We demonstrate that this nuclear receptor subfamily can regulate the expression of the CRF and POMC genes by interacting with a specific cis-acting sequence in their proximal promoter regions. To examine the physiological significance of this response, we have focused on the POMC gene. We provide evidence that nurr1 and nur77 are rapidly induced by CRF in primary pituitary cells and that this induction is mimicked by forskolin in an anterior pituitary cell line. Further, we demonstrate that both nurr1- and forskolin-dependent induction of a POMC-chloramphenicol acetyltransferase reporter gene are inhibited by mutation of the nurr1-binding site within the POMC promoter and that this site alone can confer cAMP responsiveness to a heterologous promoter. Finally, we provide evidence that the nurr1/nur77 response sequence is pivotal to both nurr1/nur77-dependent positive regulation and glucocorticoid receptor-dependent negative regulation of the POMC gene. These data strongly support the conclusion that the nurr1/nur77 subfamily plays an important coordinate neuroendocrine-regulatory role at all levels of the hypothalamic/pituitary/adrenal axis.
Murphy
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Department of Cell Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
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D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D005576:Colforsin / Q000494:pharmacology; D003346:Corticotropin-Releasing Hormone / Q000096:biosynthesis / Q000235:genetics* / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000502:physiology*; D003907:Dexamethasone / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D017930:Genes, Reporter; D007030:Hypothalamo-Hypophyseal System / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D005810:Multigene Family; D009419:Nerve Tissue Proteins / Q000502:physiology; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D010911:Pituitary Neoplasms / Q000473:pathology; D010913:Pituitary-Adrenal System / Q000502:physiology; D011333:Pro-Opiomelanocortin / Q000096:biosynthesis / Q000235:genetics*; D011401:Promoter Regions, Genetic; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics; D014157:Transcription Factors / Q000502:physiology*; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D009419:Nerve Tissue Proteins; C539818:Nr4a1 protein, mouse; C539883:Nr4a2 protein, mouse; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D005576:Colforsin; D011333:Pro-Opiomelanocortin; D003907:Dexamethasone; D003346:Corticotropin-Releasing Hormone; D000262:Adenylyl Cyclases