Truss M, Chalepakis G, Piña B, Barettino D, Brüggemeier U, Kalff M, Slater E P, Beato M
Institut für Molekularbiologie und Tumorforschung, Marburg, Fed. Rep. Germany.
J Steroid Biochem Mol Biol. 1992 Mar;41(3-8):241-8. doi: 10.1016/0960-0760(92)90350-r.
Gene regulation by steroid hormones leads to induction or repression of particular sets of genes. These effects are mediated by intracellular hormone receptors that, in the unliganded state, are maintained in an inactive form by unknown mechanisms possibly involving association with other cellular proteins. Induction of the mouse mammary tumor virus (MMTV) requires binding of the hormone receptor to a complex hormone-responsive element (HRE) located between 75 and 190 bp upstream from the start of transcription. The interaction of several receptor molecules with the four receptor binding sites in the HRE is highly cooperative on circular DNA molecules and each individual site is needed for optimal induction. In chromatin the HRE is precisely organized in phased nucleosomes. Following hormone treatment and receptor binding, changes in chromatin structure are detected that correlate with binding of transcription factors, including nuclear factor I, to the MMTV promoter. However, though nuclear factor I acts as a basal transcription factor on the MMTV promoter it does not cooperate with the hormone receptors in terms of binding to free DNA, and mutation of the nuclear factor I binding site does not eliminate hormonal stimulation. This residual induction is mediated by octamer motifs, upstream of the TATA box, that bind the ubiquitous transcription factor OTF-1. Mutation of these octamer motifs does not influence basal transcription in vitro, but completely abolishes the stimulatory effect of progesterone receptor.
类固醇激素介导的基因调控会导致特定基因集的诱导或抑制。这些效应是由细胞内激素受体介导的，在未结合配体的状态下，这些受体通过未知机制保持无活性形式，这些机制可能涉及与其他细胞蛋白的结合。小鼠乳腺肿瘤病毒（MMTV）的诱导需要激素受体与位于转录起始点上游75至190 bp之间的复杂激素反应元件（HRE）结合。在环状DNA分子上，几个受体分子与HRE中的四个受体结合位点的相互作用具有高度协同性，并且每个单独的位点对于最佳诱导都是必需的。在染色质中，HRE精确地组织在相位核小体中。激素处理和受体结合后，会检测到染色质结构的变化，这些变化与转录因子（包括核因子I）与MMTV启动子的结合相关。然而，尽管核因子I在MMTV启动子上作为基础转录因子起作用，但在与游离DNA结合方面它不与激素受体协同，并且核因子I结合位点的突变不会消除激素刺激。这种残余诱导是由TATA框上游的八聚体基序介导的，这些基序结合普遍存在的转录因子OTF-1。这些八聚体基序的突变不会影响体外的基础转录，但会完全消除孕酮受体的刺激作用。
