| Composite glucocorticoid regulation at a functionally defined negative glucocorticoid response element of the human corticotropin-releasing hormone gene. | |
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MedLine Citation:
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PMID: 10517666 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Glucocorticoid-dependent negative feedback of the hypothalamic-pituitary-adrenal axis is mediated in part through direct inhibition of hypothalamic CRH gene transcription. In the present study, we sought to further localize and characterize glucocorticoid receptor (GR) and AP-1 interactions at a functionally defined negative glucocorticoid response element (nGRE) of the CRH promoter. Transient transfection studies in mouse corticotroph AtT-20 cells demonstrated that internal deletion of the nGRE (-278 to -249 nucleotides) within the context of 1 kb of the intact CRH promoter resulted in decreased 8-BrcAMP stimulation and glucocorticoid-dependent repression of CRH promoter activity. The nGRE conferred transcriptional activation by both cAMP and overexpressed c-jun or c-fos AP-1 nucleoproteins as well as specific glucocorticoid-dependent repression to a heterologous promoter. A similar profile of regulation was observed for the composite GRE derived from mouse proliferin promoter. The CRH nGRE was clearly distinct from the consensus cAMP response element (CRE) at -224 nucleotides, which increased basal activity and cAMP responsiveness of a heterologous promoter but did not confer glucocorticoid-dependent repression. High-affinity binding sites for both GR and AP-1 nucleoproteins were identified at adjacent elements within the nGRE. Mutations that disrupted either GR or AP-1 binding activity were associated with loss of glucocorticoid-dependent repression. These results are consistent with a composite mechanism of glucocorticoid-dependent repression involving direct DNA binding of GR and AP-1 nucleoproteins at discrete adjacent sites within the CRH promoter. |
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Authors:
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S P Malkoski; R I Dorin |
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Publication Detail:
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Type: Journal Article; Research Support, U.S. Gov't, Non-P.H.S. |
Journal Detail:
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Title: Molecular endocrinology (Baltimore, Md.) Volume: 13 ISSN: 0888-8809 ISO Abbreviation: Mol. Endocrinol. Publication Date: 1999 Oct |
Date Detail:
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Created Date: 1999-12-22 Completed Date: 1999-12-22 Revised Date: 2008-11-21 |
Medline Journal Info:
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Nlm Unique ID: 8801431 Medline TA: Mol Endocrinol Country: UNITED STATES |
Other Details:
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Languages: eng Pagination: 1629-44 Citation Subset: IM |
Affiliation:
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Department of Medicine, Albuquerque Veterans Administration Medical Center, New Mexico 87108, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Base Sequence Binding Sites Cell Line Conserved Sequence Corticotropin-Releasing Hormone / genetics*, metabolism Cyclic AMP / metabolism Cyclic AMP Response Element-Binding Protein / genetics, metabolism Genes, fos Genes, jun Glucocorticoids / metabolism* Humans Luciferases / genetics, metabolism Mice Mutation Pituitary Gland, Anterior / cytology, metabolism Promoter Regions, Genetic Receptors, Glucocorticoid / genetics, metabolism Recombinant Proteins / genetics, metabolism Regulatory Sequences, Nucleic Acid Response Elements / physiology* Sequence Deletion Transcription Factor AP-1 / metabolism Transcription, Genetic |
| Chemical | |
Reg. No./Substance:
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0/Cyclic AMP Response Element-Binding Protein; 0/Glucocorticoids; 0/Receptors, Glucocorticoid; 0/Recombinant Proteins; 0/Transcription Factor AP-1; 60-92-4/Cyclic AMP; 9015-71-8/Corticotropin-Releasing Hormone; EC 1.13.12.-/Luciferases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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