Lahuna O, Fernandez L, Karlsson H, Maiter D, Lemaigre F P, Rousseau G G, Gustafsson J, Mode A
Hormone and Metabolic Research Unit, International Institute of Cellular and Molecular Pathology and Louvain University Medical School, 75 Avenue Hippocrate, B-1200 Brussels, Belgium.
Proc Natl Acad Sci U S A. 1997 Nov 11;94(23):12309-13. doi: 10.1073/pnas.94.23.12309.
Growth hormone (GH) binding to its receptor modulates gene transcription by influencing the amount or activity of transcription factors. In the rat, GH exerts sexually dimorphic effects on liver gene transcription through its pattern of secretion which is intermittent in males and continuous in females. The expression of the CYP2C12 gene coding for the female-specific cytochrome P450 2C12 protein is dependent on the continuous exposure to GH. To identify the transcription factor(s) that mediate(s) this sex-dependent GH effect, we studied the interactions of the CYP2C12 promoter with liver nuclear proteins obtained from male and female rats and from hypophysectomized animals treated or not by continuous GH infusion. GH treatment induced the binding of a protein that we identified as hepatocyte nuclear factor (HNF) 6, the prototype of a novel class of homeodomain transcription factors. HNF-6 competed with HNF-3 for binding to the same site in the CYP2C12 promoter. This HNF-6/HNF-3 binding site conveyed both HNF-6- and HNF-3-stimulated transcription of a reporter gene construct in transient cotransfection experiments. Electrophoretic mobility shift assays showed more HNF-6 DNA-binding activity in female than in male liver nuclear extracts. Liver HNF-6 mRNA was barely detectable in the hypophysectomized rats and was restored to normal levels by GH treatment. This work provides an example of a homeodomain-containing transcription factor that is GH-regulated and also reports on the hormonal regulation of HNF-6.
生长激素（GH）与其受体结合，通过影响转录因子的数量或活性来调节基因转录。在大鼠中，GH通过其分泌模式对肝脏基因转录产生性别差异效应，雄性大鼠的分泌模式是间歇性的，而雌性大鼠是持续性的。编码雌性特异性细胞色素P450 2C12蛋白的CYP2C12基因的表达依赖于持续暴露于GH。为了确定介导这种性别依赖性GH效应的转录因子，我们研究了CYP2C12启动子与从雄性和雌性大鼠以及经或未经持续GH输注治疗的垂体切除动物获得的肝核蛋白之间的相互作用。GH处理诱导了一种蛋白质的结合，我们将其鉴定为肝细胞核因子（HNF）6，这是一类新型同源结构域转录因子的原型。HNF-6与HNF-3竞争结合CYP2C12启动子中的同一位点。在瞬时共转染实验中，这个HNF-6/HNF-3结合位点传递了HNF-6和HNF-3刺激的报告基因构建体的转录。电泳迁移率变动分析显示，雌性肝核提取物中的HNF-6 DNA结合活性高于雄性。垂体切除的大鼠肝脏中几乎检测不到HNF-6 mRNA，而GH处理可使其恢复到正常水平。这项工作提供了一个受GH调节的含同源结构域转录因子的例子，同时也报道了HNF-6的激素调节。
