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Mol Cell Biol, July 1998, p. 3744-3751, Vol. 18, No. 7
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Cyclosporin A-Sensitive Transcription Factor Egr-3 Regulates Fas Ligand Expression

Paul R. Mittelstadt and Jonathan D. Ashwell*

Laboratory of Immune Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-1152

Received 3 February 1998/Returned for modification 16 March 1998/Accepted 3 April 1998

Activation-induced transcriptional upregulation of the ligand for Fas (FasL) and the resulting apoptosis of Fas-bearing cells constitute essential steps in a host of normal and pathological processes. Here we describe an activation-inducible cis-acting regulatory element in the fasL promoter that is required for gene expression. Oligonucleotide competition and antibody supershift analyses identified two activation-induced DNA-binding species: Egr-1 (NGFI-A, krox-24, zif268, TIS-8), a transcription factor that has been implicated in growth, differentiation, and apoptosis; and Egr-3 (PILOT), a transcription factor of no previously known function. Activation-induced expression of Egr-3, like that of FasL, was inhibited by cyclosporin A, whereas expression of Egr-1 was unaffected. Transient expression of Egr-3 alone increased fasL promoter activity in a cyclosporin A-insensitive manner, whereas expression of Egr-1 had little effect. Moreover, endogenous fasL mRNA was induced in nonlymphoid cells by forced expression of Egr-3 in the absence of any other stimulus. These studies identify a critical Egr family-binding site in the fasL promoter and demonstrate that activation-induced Egr-3, but not Egr-1, directly upregulates fasL transcription in response to activating stimuli.

* Corresponding author. Mailing address: Laboratory of Immune Cell Biology, National Cancer Institute, National Institutes of Health, Bldg. 10, Room 1B-40, Bethesda, MD 20892-1152. Phone: (301) 496-4931. Fax: (301) 402-4844. E-mail: jda{at}Box-j.nih.gov.

Mol Cell Biol, July 1998, p. 3744-3751, Vol. 18, No. 7
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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