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Molecular and Cellular Biology, December 1998, p. 7166-7175, Vol. 18, No. 12
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

The Notch Pathway Intermediate HES-1 Silences CD4 Gene Expression

Han K. Kim and Gerald Siu*

Department of Microbiology, Columbia University College of Physicians and Surgeons, New York, New York 10032

Received 24 April 1998/Returned for modification 15 May 1998/Accepted 10 September 1998

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.

* Corresponding author. Mailing address: Department of Microbiology, Columbia University College of Physicians and Surgeons, 701 West 168th St., New York, NY 10032. Phone: (212) 305-2743. Fax: (212) 305-8013. E-mail: siu{at}cusiu3.cpmc.columbia.edu.

Molecular and Cellular Biology, December 1998, p. 7166-7175, Vol. 18, No. 12
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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