Kim H K, Siu G
Department of Microbiology, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.
Mol Cell Biol. 1998 Dec;18(12):7166-75. doi: 10.1128/MCB.18.12.7166.
We have previously identified a transcriptional silencer that is critical for proper expression of the CD4 gene during T-cell development. Here we report that the Hairy/Enhancer of Split homologue HES-1, a transcription factor in the lin12/Notch signaling pathway, binds to an important functional site in the CD4 silencer. Overexpression of HES-1 leads to the silencer site-dependent repression of CD4 promoter and enhancer function as well as the downregulation of endogenous CD4 expression in CD4(+) CD8(-) TH cells. Interestingly, overexpression of an activated form of Notch1 (NotchIC) leads to the repression of CD4 promoter and enhancer function both in the presence and absence of the silencer. NotchIC-mediated CD4 silencer function is not affected by the deletion of the HES-1-binding site, indicating that multiple factors binding to CD4 transcriptional control elements are responsive to signaling from this pathway, including other silencer-binding factors. Taken together, these data are consistent with the hypothesis that the lin12/Notch signaling pathway is important in thymic development and provide a molecular mechanism via the control of CD4 gene expression in which the lin12/Notch pathway affects T-cell developmental fate.
我们之前鉴定出一种转录沉默子，它对于T细胞发育过程中CD4基因的正常表达至关重要。在此我们报告，Hairy/Enhancer of Split同源物HES-1（lin12/Notch信号通路中的一种转录因子）与CD4沉默子中的一个重要功能位点结合。HES-1的过表达导致沉默子位点依赖性的CD4启动子和增强子功能的抑制，以及CD4(+) CD8(-) TH细胞中内源性CD4表达的下调。有趣的是，活化形式的Notch1（NotchIC）的过表达在有或无沉默子的情况下均导致CD4启动子和增强子功能的抑制。NotchIC介导的CD4沉默子功能不受HES-1结合位点缺失的影响，这表明与CD4转录控制元件结合的多种因子对该信号通路的信号有反应，包括其他沉默子结合因子。综上所述，这些数据与lin12/Notch信号通路在胸腺发育中很重要这一假设一致，并通过控制CD4基因表达提供了一种分子机制，其中lin12/Notch通路影响T细胞发育命运。
