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Published 5 August 2002. doi:10.1083/jcb.200201106
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© The Rockefeller University Press, 0021-9525/2002/8/519 $5.00
The Journal of Cell Biology, Volume 158, Number 3, August 5, 2002 519-528

Article

Distinct cell death pathways triggered by the adenovirus early region 4 ORF 4 protein



Amélie Robert1, Marie-Joëlle Miron2, Claudia Champagne1, Marie-Claude Gingras1, Philip E. Branton2,3 and Josée N. Lavoie1

1 Centre de recherche en cancérologie de l'Université Laval, L'Hôtel-Dieu de Québec, CHUQ, Québec G1R 2J6, Canada
2 Department of Biochemistry, McGill University, Montreal, Québec H3G 1Y6, Canada
3 the McGill Cancer Centre, McGill University, Montreal, Québec H3G 1Y6, Canada

Address correspondence to Dr. Josée N. Lavoie, CRC, L'Hôtel-Dieu de Québec, CHUQ, St-Patrick, 9 rue McMahon, Québec G1R 2J6, Canada. Tel.: (418) 525-4444 ext. 5120. Fax: (418) 691-5439. E-mail: josee.lavoie{at}crhdq.ulaval.ca

In transformed cells, induction of apoptosis by adenovirus type 2 (Ad2) early region 4 ORF 4 (E4orf4) correlates with accumulation of E4orf4 in the cell membrane–cytoskeleton fraction. However, E4orf4 is largely expressed in nuclear regions before the onset of apoptosis. To determine the relative contribution of nuclear E4orf4 versus membrane-associated E4orf4 to cell death signaling, we engineered green fluorescent fusion proteins to target E4orf4 to specific cell compartments. The targeting of Ad2 E4orf4 to cell membranes through a CAAX-box or a myristylation consensus signal sufficed to mimic the fast Src-dependent apoptotic program induced by wild-type E4orf4. In marked contrast, the nuclear targeting of E4orf4 abolished the early induction of extranuclear apoptosis. However, nuclear E4orf4 still induced a delayed cell death response independent of Src-like activity and of E4orf4 tyrosine phosphorylation. The zVAD.fmk-inhibitable caspases were dispensable for execution of both cell death programs. Nevertheless, both pathways led to caspase activation in some cell types through the mitochondrial pathway. Finally, our data support a critical role for calpains upstream in the death effector pathway triggered by the Src-mediated cytoplasmic death signal. We conclude that Ad2 E4orf4 induces two distinct cell death responses, whose relative contributions to cell killing may be determined by the genetic background.

Key Words: Ad2 E4orf4; apoptosis; Src kinases; caspase; calpastatin


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