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C/EBP Regulates Hepatic Transcription of 11β-Hydroxysteroid Dehydrogenase Type 1

2000; Elsevier BV; Volume: 275; Issue: 39 Linguagem: Inglês

10.1074/jbc.m001286200

1083-351X

Louise Williams, Val Lyons, Iolaina MacLeod, Vidya Rajan, Gretchen J. Darlington, Valeria Poli, Jonathan R. Seckl, Karen E. Chapman,

ATP Synthase and ATPases Research

Glucocorticoid action within individual cells is potently modulated by 11beta-hydroxysteroid dehydrogenase (11beta-HSD), which, by interconverting active and inert glucocorticoids, determines steroid access to receptors. Type 1 11beta-HSD (11beta-HSD1) is highly expressed in liver where it regenerates glucocorticoids, thus amplifying their action and contributing to induction of glucocorticoid-responsive genes, most of which are also regulated by members of the C/EBP (CAAT/enhancer-binding protein) family of transcription factors. Here we demonstrate that C/EBPalpha is a potent activator of the 11beta-HSD1 gene in hepatoma cells and that mice deficient in C/EBPalpha have reduced hepatic 11beta-HSD1 expression. In contrast, C/EBPbeta is a relatively weak activator of 11beta-HSD1 transcription in hepatoma cells and attenuates C/EBPalpha induction, and mice that lack C/EBPbeta have increased hepatic 11beta-HSD1 mRNA. The 11beta-HSD1 promoter (between -812 and +76) contains 10 C/EBP binding sites, and mutation of the promoter proximal sites decreases the C/EBP inducibility of the promoter. One site encompasses the transcription start, and both C/EBPalpha and C/EBPbeta are present in complexes formed by liver nuclear proteins at this site. The regulation of 11beta-HSD1 expression, and hence intracellular glucocorticoid levels, by members of the C/EBP family provides a novel mechanism for cross-talk between the C/EBP family of transcription factors and the glucocorticoid signaling pathway.