Leung Thomas H, Hoffmann Alexander, Baltimore David
Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA.
Cell. 2004 Aug 20;118(4):453-64. doi: 10.1016/j.cell.2004.08.007.
The transcription factor NF-kappaB regulates a wide variety of genes involved in multiple processes. Although the apparent consensus sequence of DNA binding sites for NF-kappaB (kappaB sites) is very broad, the sites active in any one gene show remarkable evolutionary stability. Using a lentivirus-based methodology for implantation of gene regulatory sequences we show that for genes with two kappaB sites, both are required for activity. Swapping sites between kappaB-dependent genes altered NF-kappaB dimer specificity of the promoters and revealed that two kappaB sites can function together as a module to regulate gene activation. Further, although the sequence of the kappaB site is important for determining kappaB family member specificity, rather than determining the ability of a particular dimer to bind effectively, the sequence affects which coactivators will form productive interactions with the bound NF-kappaB dimer. This suggests that binding sites may impart a specific configuration to bound transcription factors.
转录因子NF-κB可调控参与多种过程的众多基因。尽管NF-κB（κB位点）DNA结合位点的明显共有序列非常宽泛，但在任何一个基因中具有活性的位点都表现出显著的进化稳定性。我们采用基于慢病毒的方法来植入基因调控序列，结果表明，对于具有两个κB位点的基因而言，两个位点对于活性都是必需的。在依赖κB的基因之间交换位点，改变了启动子的NF-κB二聚体特异性，并揭示出两个κB位点可作为一个模块共同发挥作用来调控基因激活。此外，尽管κB位点的序列对于确定κB家族成员特异性很重要，而不是决定特定二聚体有效结合的能力，但该序列会影响哪些共激活因子将与结合的NF-κB二聚体形成有效的相互作用。这表明结合位点可能会赋予结合的转录因子一种特定的构象。
