Laboratory of Lactation and Metabolic Physiology, Department of Animal Science, University of Vermont, Burlington, VT 05405, USA.
Int J Biochem Cell Biol. 2013 Mar;45(3):724-35. doi: 10.1016/j.biocel.2013.01.001. Epub 2013 Jan 10.
Regulation of milk protein gene expression by lactogenic hormones (prolactin and glucocorticoids) provides an attractive model for studying the mechanisms by which protein and steroid hormones synergistically regulate gene expression. β-Casein is one of the major milk proteins and its expression in mammary epithelial cells is stimulated by lactogenic hormones. The signal transducer and activator of transcription 5 and glucocorticoid receptor are essential downstream mediators of prolactin and glucocorticoid signaling, respectively. Previous studies have shown that mutating the octamer-binding site of the β-casein gene proximal promoter dramatically reduces the hormonal induction of the promoter activity. However, little is known about the underlying molecular mechanisms. In this report, we show that lactogenic hormones rapidly induce the binding of octamer-binding transcription factor-1 to the β-casein promoter and this induction is not mediated by either increasing the expression of octamer-binding transcription factor-1 or inducing its translocation to the nucleus. Rather, lactogenic hormones induce physical interactions between the octamer-binding transcription factor-1, signal transducer and activator of transcription 5, and glucocorticoid receptor to form a ternary complex, and these interactions enhance or stabilize the binding of these transcription factors to the promoter. Abolishing these interactions significantly reduces the hormonal induction of β-casein gene transcription. Thus, our study indicates that octamer-binding transcription factor-1 may serve as a master regulator that facilitates the DNA binding of both signal transducer and activator of transcription 5 and glucocorticoid receptor in hormone-induced β-casein expression, and defines a novel mechanism of regulation of tissue-specific gene expression by the ubiquitous octamer-binding transcription factor-1.
泌乳激素（催乳素和糖皮质激素）对乳蛋白基因表达的调控为研究蛋白质和甾体激素协同调节基因表达的机制提供了一个有吸引力的模型。β-酪蛋白是主要的乳蛋白之一，其在乳腺上皮细胞中的表达受泌乳激素刺激。信号转导和转录激活因子 5 和糖皮质激素受体分别是催乳素和糖皮质激素信号转导的必需下游介质。先前的研究表明，突变β-酪蛋白基因近端启动子的八聚体结合位点会显著降低启动子的激素诱导活性。然而，对于潜在的分子机制知之甚少。在本报告中，我们表明，泌乳激素可迅速诱导八聚体结合转录因子-1与β-酪蛋白启动子结合，这种诱导不是通过增加八聚体结合转录因子-1的表达或诱导其向核内易位来介导的。相反，泌乳激素诱导八聚体结合转录因子-1、信号转导和转录激活因子 5 和糖皮质激素受体之间的物理相互作用，形成三元复合物，这些相互作用增强或稳定这些转录因子与启动子的结合。消除这些相互作用会显著降低β-酪蛋白基因转录的激素诱导。因此，我们的研究表明，八聚体结合转录因子-1 可能作为一种主调控因子，促进信号转导和转录激活因子 5 和糖皮质激素受体在激素诱导的β-酪蛋白表达中的 DNA 结合，并定义了普遍存在的八聚体结合转录因子-1 调节组织特异性基因表达的新机制。
