title: Signal transduction in the hypothalamic corticotropin-releasing factor system and its clinical implications.
abstract: Corticotropin-releasing factor (CRF) is a major regulatory peptide in the hypothalamic-pituitary-adrenal (HPA) axis under stress conditions. In response to stress, CRF is produced in the hypothalamic paraventricular nucleus. Forskolin- or pituitary adenylate cyclase-activating polypeptide-stimulated CRF gene transcription is mediated by the cyclic AMP (cAMP) response element on the CRF 5'-promoter region. Estrogens enhance activation of the CRF gene in stress, while inducible cAMP-early repressor suppresses the stress response via inhibition of the cAMP-dependent CRF gene. Glucocorticoid-dependent repression of cAMP-stimulated CRF promoter activity is mediated by both the negative glucocorticoid-response element and the serum-response element, while interleukin-6 (IL-6) stimulates the CRF gene. Suppressor of cytokine signaling-3, stimulated by IL-6 and cAMP, is involved in the negative regulation of CRF gene expression. Such complex mechanisms contribute to stress responses and homeostasis in the hypothalamus. Moreover, disruption of the HPA axis may cause a number of diseases related to stress. For example, CRF-induced p21-activated kinase 3 mRNA expression may be related to the proliferation of corticotrophs in Nelson's syndrome. A higher molecular weight form of immunoreactive β-endorphin, putative proopiomelanocortin (POMC), is increased in CRF-knockout mice, suggesting the important role of CRF in the processing of POMC through changes in prohormone convertase type-1 expression levels.
authors: Department of Endocrinology and Metabolism, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan. kkageyama@hkg.odn.ne.jp
authors: Kazunori
authors: K
authors: Kageyama
authors: Naoki
authors: N
authors: Tamasawa
authors: Toshihiro
authors: T
authors: Suda
mesh_terms: D000818:Animals; D003346:Corticotropin-Releasing Hormone / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D000242:Cyclic AMP / Q000378:metabolism; D005938:Glucocorticoids / Q000502:physiology; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000502:physiology*; D007031:Hypothalamus / Q000378:metabolism*; D015850:Interleukin-6 / Q000502:physiology; D051379:Mice; D009347:Nelson Syndrome / Q000503:physiopathology; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000502:physiology; D010913:Pituitary-Adrenal System / Q000502:physiology*; D011333:Pro-Opiomelanocortin; D015398:Signal Transduction; D013315:Stress, Psychological / Q000503:physiopathology*; D050826:Suppressor of Cytokine Signaling Proteins / Q000502:physiology; D018808:Transcription Factor AP-1 / Q000502:physiology
chemical_list: C495402:Adcyap1 protein, mouse; D005938:Glucocorticoids; D015850:Interleukin-6; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D050826:Suppressor of Cytokine Signaling Proteins; D018808:Transcription Factor AP-1; D011333:Pro-Opiomelanocortin; D003346:Corticotropin-Releasing Hormone; D000242:Cyclic AMP