Molecular mechanisms for corticotropin-releasing hormone gene repression by glucocorticoid in BE(2)C neuronal cell line.
The molecular mechanisms for the suppression of corticotropin-releasing hormone (CRH) gene expression by glucocorticoid remain to be clarified albeit the well-known physiological role of the glucocorticoid-induced negative feedback regulation of the gene. In this study, we examined the effect of glucocorticoid on CRH gene transcription using the human BE(2)C neuronal cell line, which expresses the CRH gene and produces CRH peptide intrinsically. Dexamethasone, a specific ligand for the glucocorticoid receptor (GR), potently suppressed human CRH 5'-promoter activity. The effect was GR-dependent, and was completely antagonized by antiglucocorticoid RU38486. Treatment with neither sodium butyrate nor trichostatin A abolished the suppression, thus making the possible involvement of histone deacetylase (HDACs) unlikely. The suppression was not influenced by the deletion or mutation of the proposed negative glucocorticoid-response element (nGRE) but was completely eliminated by that of cAMP-response element. Finally, overexpression of protein kinase A catalytic subunit antagonized the glucocorticoid suppression, whereas overexpression of GR enhanced it. Taken together, our data suggest that: (1) glucocorticoid exerts its negative effect on CRH gene transcription in a GR-dependent manner, but the GR-mediated inhibition appears to be independent of the nGRE; (2) HDACs do not play a significant role in the glucocorticoid repression; (3) some of the inhibitory events may take place through transrepression of protein kinase A by GR.
Yamamori
Etsuko
E
Department of Medicine, Nagoya University Graduate School of Medicine and Hospital, Nagoya 466-8550, Japan.
Iwasaki
Yasumasa
Y
Taguchi
Takafumi
T
Nishiyama
Mitsuru
M
Yoshida
Masanori
M
Asai
Masato
M
Oiso
Yutaka
Y
Itoi
Keiichi
K
Kambayashi
Machiko
M
Hashimoto
Kozo
K
D045744:Cell Line, Tumor; D003346:Corticotropin-Releasing Hormone / Q000096:biosynthesis* / Q000235:genetics; D017868:Cyclic AMP-Dependent Protein Kinases / Q000096:biosynthesis / Q000235:genetics; D003907:Dexamethasone / Q000494:pharmacology*; D005938:Glucocorticoids / Q000378:metabolism / Q000494:pharmacology*; D006727:Hormone Antagonists / Q000494:pharmacology; D006801:Humans; D015735:Mifepristone / Q000494:pharmacology; D009474:Neurons / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism; D020218:Response Elements / Q000502:physiology*; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology
D005938:Glucocorticoids; D006727:Hormone Antagonists; D011965:Receptors, Glucocorticoid; D015735:Mifepristone; D003907:Dexamethasone; D003346:Corticotropin-Releasing Hormone; D017868:Cyclic AMP-Dependent Protein Kinases