Flanking sequence composition differentially affects the binding and functional characteristics of glucocorticoid receptor homo- and heterodimers.
Flanking sequence composition differentially affects the binding and functional characteristics of glucocorticoid receptor homo- and heterodimers.
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侧翼序列组成不同地影响糖皮质激素受体同二聚体和异二聚体的结合和功能特征。
DOI：
10.1021/bi060314k
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发表时间：
2006
期刊：
影响因子：
2.9
通讯作者：
Holland,LenéJ
中科院分区：
文献类型：
--
作者：
Morin,Brian;Nichols,LaNitaA;Holland,LenéJ
许多转录因子的核心结合位点已经被鉴定和表征，但这些序列不能完全解释细胞特异性和基因特异性控制基因转录的细微差别。许多因素可能有助于基因对特定转录调节蛋白的精确反应，包括该蛋白核心结合位点附近的核苷酸。在这里，我们研究了相邻γ-纤维蛋白原基因调控区域的两个侧翼序列，该区域结合异种糖皮质激素受体辅助因子（XGRAF）和糖皮质激素受体（GR）的异源二聚体。上游侧翼突变导致XGRAF结合水平降低，但激素诱导变化不大。然而，靠近GR结合位点的下游侧翼的改变导致GR单体结合和激素诱导水平的降低。将XGRAF−GR结合位点转化为一个完整的糖皮质激素反应元件（GRE）改变了侧翼序列的作用。在这个位置上，一个完整的GRE需要野生型上游侧翼结合GR同二聚体并诱导转录达到最大水平。相反，下游侧翼的突变对GR二聚体的结合和功能都没有损害。因此，侧翼序列组成和二聚体伴侣共同影响GR功能，强调了鉴定真实转录因子应答元件的复杂性。
The core binding sites for a multitude of transcription factors have been identified and characterized, but these sequences cannot fully account for the nuances of cell-specific and gene-specific control of gene transcription. Many factors may contribute to the precise responsiveness of a gene to a particular transcriptional regulatory protein, including the nucleotides in the proximity of the core binding site for that protein. Here, we examine two flanking sequences bordering a site in the γ-fibrinogen gene regulatory region that binds a heterodimer of theXenopusglucocorticoid receptor accessory factor (XGRAF) and the glucocorticoid receptor (GR). Mutation of the upstream flank results in a decrease in the level of XGRAF binding but little change in hormone induction. However, alteration of the downstream flank adjacent to the GR binding site causes a decrease in levels of both GR monomer binding and hormone induction. Conversion of the XGRAF−GR binding site to a full glucocorticoid response element (GRE) alters the role of the flanking sequences. A full GRE in this position requires the wild-type upstream flank to bind GR homodimer and induce transcription to maximal levels. In contrast, mutation of the downstream flank is not detrimental to either the binding or the function of the GR dimer. Thus, flanking sequence composition and dimer partner combine to influence GR function, underscoring the complexities involved in the identification of authentic transcription factor response elements.