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Molecular and Cellular Biology, March 1999, p. 2098-2108, Vol. 19, No. 3
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Activation-Dependent Transcriptional Regulation of the Human fas Promoter Requires NF-kappa B p50-p65 Recruitment

Henry Chan, David P. Bartos, and Laurie B. Owen-Schaub*

Department of Immunology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030

Received 19 June 1998/Returned for modification 14 August 1998/Accepted 10 December 1998

Fas (CD95) and Fas ligand (CD95L) are an interacting receptor-ligand pair required for immune homeostasis. Lymphocyte activation results in the upregulation of Fas expression and the acquisition of sensitivity to FasL-mediated apoptosis. Although Fas upregulation is central to the preservation of immunologic tolerance, little is known about the molecular machinery underlying this process. To investigate the events involved in activation-induced Fas upregulation, we have examined mRNA accumulation, fas promoter activity, and protein expression in the Jurkat T-cell line treated with phorbol myristate acetate and ionomycin (P/I), pharmacological mimics of T-cell receptor activation. Although resting Jurkat cells express Fas, Fas mRNA was induced approximately 10-fold in 2 h upon P/I stimulation. Using sequential deletion mutants of the human fas promoter in transient transfection assays, we identified a 47-bp sequence (positions -306 to -260 relative to the ATG) required for activation-driven fas upregulation. Sequence analysis revealed the presence of a previously unrecognized composite binding site for both the Sp1 and NF-kappa B transcription factors at positions -295 to -286. Electrophoretic mobility shift assay (EMSA) and supershift analyses of this region documented constitutive binding of Sp1 in unactivated nuclear extracts and inducible binding of p50-p65 NF-kappa B heterodimers after P/I activation. Sp1 and NF-kappa B transcription factor binding was shown to be mutually exclusive by EMSA displacement studies with purified recombinant Sp1 and recombinant p50. The functional contribution of the kappa B-Sp1 composite site in P/I-inducible fas promoter activation was verified by using kappa B-Sp1 concatamers (-295 to -286) in a thymidine kinase promoter-driven reporter construct and native promoter constructs in Jurkat cells overexpressing Ikappa B-alpha . Site-directed mutagenesis of the critical guanine nucleotides in the kappa B-Sp1 element documented the essential role of this site in activation-dependent fas promoter induction.

* Corresponding author. Mailing address: The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Box 178, Houston, TX 77030. Phone: (713) 792-8735. Fax: (713) 745-1633. E-mail: lowensch{at}mdanderson.org.

Molecular and Cellular Biology, March 1999, p. 2098-2108, Vol. 19, No. 3
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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