The notch pathway intermediate HES-1 silences CD4 gene expression.
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.
Kim
H K
HK
Department of Microbiology, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.
Siu
G
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D000818:Animals; D015704:CD4 Antigens / Q000235:genetics*; D003432:Cross-Linking Reagents / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics*; D017930:Genes, Reporter; D018398:Homeodomain Proteins / Q000235:genetics*; D008322:Mammals; D008565:Membrane Proteins / Q000235:genetics*; D009687:Nuclear Proteins / Q000032:analysis; D009838:Oligodeoxyribonucleotides / Q000235:genetics; D051880:Receptors, Notch; D015398:Signal Transduction / Q000235:genetics*; D016329:Sp1 Transcription Factor / Q000235:genetics; D013601:T-Lymphocytes / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics; D014162:Transfection / Q000235:genetics; D014466:Ultraviolet Rays
D015704:CD4 Antigens; D003432:Cross-Linking Reagents; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D008565:Membrane Proteins; D009687:Nuclear Proteins; D009838:Oligodeoxyribonucleotides; D051880:Receptors, Notch; D016329:Sp1 Transcription Factor