Transcriptional Regulatin of the CYP2C12 Gene in Female Rats

摘要

The purpose of this study was to clarify the mechanism (s) responsible for the growth hormone (GH)-induced expression of the CYP2C12 gene. to identify a functional GH-responsive element (GHRE) in vivo, we perfomed the direct injection of promoter-luciferase chimeric genes into female rat livers. The resutls showed that the luciferase activity was decreased to aproximately 20% by the deletion of the sequence betwen nucleotides -4213 and -4261. Within this regin, two copies of a possible GHRE were present. The sequence of the GHRE wa overlapped with that of an interferon-#gamma#-activated sequence (GAS), known to be recognized by the signal transducer and activator of transicription (STAT) proteins. In fact, a super shift assay showed that STAT5 was capable of binding to the core sequence of the GHRE. Furthermore, a luciferase assay with reprter plasmids, which lacks HNF4- or NHF6-binding sites, revealed that the GH-stimulated expression of the CYP2C12 gene ewas regulated cooperatiely by STAT5, HNF-4, HNF-6 and the factor(s) which binds to the elements, 2C12-I (-4095 to -4074) and 2C12-II (4072 to -4045). The coopeatie regulation by STAT5 and the liver-enriched transcription factors account for the GH-dependent and the lier-specific expression of the CYP2C12 gene in female rats.