Novel glucocorticoid and cAMP interactions on the CRH gene promoter.
Glucocorticoids inhibit corticotrophin releasing hormone (CRH) production in the hypothalamus but stimulate production from the placenta. We have sought to identify the key elements regulating the CRH gene. Mouse pituitary tumour-derived cells (AtT20 cells) were used in deletion and mutational analyses of the CRH promoter. Two cAMP responsive elements were identified: (I) a consensus cAMP response element (CRE) and (II) a previously unrecognised caudal-type homeobox response element (CDXRE). Glucocorticoids inhibit only the component of cAMP-stimulation occurring via the CRE through an action involving a negative glucocorticoid response element (nGRE). We also identified two regions that, in the absence of the nGRE, can be stimulated by glucocorticoids: (I) the CRE and (II) a region between -213 and -99 bps. Electrophoretic mobility shift assays (EMSAs) identified binding of the transcription factors CREB and Fos at the CRE in AtT20 cells while CREB and cJun were detected in placental cells. Tissue specific expression of transcription factors may mediate regulation of the CRH gene.
King
Bruce R
BR
Mothers and Babies Research Centre, Hunter Medical Research Institute, John Hunter Hospital, University of Newcastle, Newcastle, NSW 2310, Australia.
Smith
Roger
R
Nicholson
Richard C
RC
D000818:Animals; D003346:Corticotropin-Releasing Hormone / Q000187:drug effects / Q000235:genetics*; D000242:Cyclic AMP / Q000494:pharmacology*; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology*; D051379:Mice; D016297:Mutagenesis, Site-Directed; D010902:Pituitary Gland / Q000166:cytology; D010920:Placenta / Q000166:cytology; D011401:Promoter Regions, Genetic / Q000235:genetics*; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism; D020218:Response Elements; D014162:Transfection; D014407:Tumor Cells, Cultured
D017362:Cyclic AMP Response Element-Binding Protein; D005938:Glucocorticoids; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D003346:Corticotropin-Releasing Hormone; D000242:Cyclic AMP