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Molecular and Cellular Biology, August 2001, p. 5299-5305, Vol. 21, No. 16
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.16.5299-5305.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

NF-kappa B Signals Induce the Expression of c-FLIP

Olivier Micheau,1 Susanne Lens,1 Olivier Gaide,1 Kostis Alevizopoulos,2 and Jürg Tschopp1,*

Institute of Biochemistry, University of Lausanne, BIL Biomedical Research Center,1 and Apotech Biochemicals, Biopôle,2 CH-1066 Epalinges, Switzerland

Received 1 February 2001/Returned for modification 16 March 2001/Accepted 24 May 2001

Activation of the transcription factor NF-kappa B is a major effector of the inducible resistance to death receptor-mediated apoptosis. Previous evidence indicates that the combined transcriptional activation of TRAF-1, TRAF-2, IAP-1, and IAP-2 is required to suppress cell death by tumor necrosis factor (TNF). Here we show that NF-kappa B activation upregulates the caspase 8 inhibitor FLIP, resulting in increased resistance to Fas ligand (FasL) or TNF. Restoration of either the full-length 55-kDa long form of FLIP or an alternatively spliced short form of FLIP in NF-kappa B null cells inhibits TNF- and FasL-induced cell death efficiently, whereas the expression of IAP or TRAF family members only partially rescues cells from death. Resistance to either FasL- or TNF-induced apoptosis is overcome when cells are incubated in the presence of the protein synthesis inhibitor cycloheximide. This treatment leads to the rapid downregulation of FLIP but not to that of TRAF2. Our findings suggest that FLIP is an important mediator of NF-kappa B-controlled antiapoptotic signals.

* Corresponding author. Mailing address: Institute of Biochemistry, University of Lausanne, Ch. des Boveresses 155, CH-1066 Epalinges, Switzerland. Phone: 41 21 692 5738. Fax: 41 21 692 5705. E-mail: jurg.tschopp{at}ib.unil.ch.

Molecular and Cellular Biology, August 2001, p. 5299-5305, Vol. 21, No. 16
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.16.5299-5305.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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