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Journal of Virology, February 2003, p. 2651-2662, Vol. 77, No. 4
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.4.2651-2662.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

E1A Sensitizes Cells to Tumor Necrosis Factor Alpha by Downregulating c-FLIPS

Denise Perez1 and Eileen White1,2,3,4*

Center for Advanced Biotechnology and Medicine,1 Howard Hughes Medical Institute,2 Department of Molecular Biology and Biochemistry,3 Cancer Institute of New Jersey, Rutgers University, Piscataway, New Jersey 088544

Received 10 September 2002/ Accepted 14 November 2002

Tumor necrosis factor alpha (TNF-{alpha}) activates both apoptosis and NF-{kappa}B-dependent survival pathways, the former of which requires inhibition of gene expression to be manifested. c-FLIP is a TNF-{alpha}-induced gene that inhibits caspase-8 activation during TNF-{alpha} signaling. Adenovirus infection and E1A expression sensitize cells to TNF-{alpha} by allowing apoptosis in the absence of inhibitors of gene expression, suggesting that it may be disabling a survival signaling pathway. E1A promoted TNF-{alpha}-mediated activation of caspase-8, suggesting that sensitivity was occurring at the level of the death-inducing signaling complex. Furthermore, E1A expression downregulated c-FLIPS expression and prevented its induction by TNF-{alpha}. c-FLIPS and viral FLIP expression rescued E1A-mediated sensitization to TNF-{alpha} by restoring the resistance of caspase-8 to activation, thereby preventing cell death. E1A inhibited TNF-{alpha}-dependent induction of c-FLIPS mRNA and stimulated ubiquitination- and proteasome-dependent degradation of c-FLIPS protein. Since elevated c-FLIP levels confer resistance to apoptosis and promote tumorigenicity, interference with its induction by NF-{kappa}B and stimulation of its destruction in the proteasome may provide novel therapeutic approaches for facilitating the elimination of apoptosis-refractory tumor cells.

* Corresponding author. Mailing address: Rutgers University, 679 Hoes Lane, Room 140, Piscataway, NJ 08854. Phone: (732) 235-5329. Fax: (732) 235-5795. E-mail: ewhite{at}cabm.rutgers.edu.

Journal of Virology, February 2003, p. 2651-2662, Vol. 77, No. 4
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.4.2651-2662.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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