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.
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5 August 2002
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August 05 2002
Distinct cell death pathways triggered by the adenovirus early region 4 ORF 4 protein
Amélie Robert,
Amélie Robert
1Centre de recherche en cancérologie de l'Université Laval, L'Hôtel-Dieu de Québec, CHUQ, Québec G1R 2J6, Canada
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Marie-Joëlle Miron,
Marie-Joëlle Miron
2Department of Biochemistry, McGill University, Montreal, Québec H3G 1Y6, Canada
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Claudia Champagne,
Claudia Champagne
1Centre de recherche en cancérologie de l'Université Laval, L'Hôtel-Dieu de Québec, CHUQ, Québec G1R 2J6, Canada
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Marie-Claude Gingras,
Marie-Claude Gingras
1Centre de recherche en cancérologie de l'Université Laval, L'Hôtel-Dieu de Québec, CHUQ, Québec G1R 2J6, Canada
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Philip E. Branton,
Philip E. Branton
2Department of Biochemistry, McGill University, Montreal, Québec H3G 1Y6, Canada
3the McGill Cancer Centre, McGill University, Montreal, Québec H3G 1Y6, Canada
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Josée N. Lavoie
Josée N. Lavoie
1Centre de recherche en cancérologie de l'Université Laval, L'Hôtel-Dieu de Québec, CHUQ, Québec G1R 2J6, Canada
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Amélie Robert
1Centre de recherche en cancérologie de l'Université Laval, L'Hôtel-Dieu de Québec, CHUQ, Québec G1R 2J6, Canada
Marie-Joëlle Miron
2Department of Biochemistry, McGill University, Montreal, Québec H3G 1Y6, Canada
Claudia Champagne
1Centre de recherche en cancérologie de l'Université Laval, L'Hôtel-Dieu de Québec, CHUQ, Québec G1R 2J6, Canada
Marie-Claude Gingras
1Centre de recherche en cancérologie de l'Université Laval, L'Hôtel-Dieu de Québec, CHUQ, Québec G1R 2J6, Canada
Philip E. Branton
2Department of Biochemistry, McGill University, Montreal, Québec H3G 1Y6, Canada
3the McGill Cancer Centre, McGill University, Montreal, Québec H3G 1Y6, Canada
Josée N. Lavoie
1Centre de recherche en cancérologie de l'Université Laval, L'Hôtel-Dieu de Québec, CHUQ, Québec G1R 2J6, 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: [email protected]
*
Abbreviations used in this paper: Ad2, adenovirus type 2; AIF, apoptosis-inducing factor; E4orf4, early region 4 ORF 4; Myr, myristylation; NES, nuclear exclusion signal; PP, protein phosphatase; WT, wild-type.
Online ISSN: 1540-8140
Print ISSN: 0021-9525
The Rockefeller University Press
2002
J Cell Biol (2002) 158 (3): 519–528.
Citation
Amélie Robert, Marie-Joëlle Miron, Claudia Champagne, Marie-Claude Gingras, Philip E. Branton, Josée N. Lavoie; Distinct cell death pathways triggered by the adenovirus early region 4 ORF 4 protein . J Cell Biol 5 August 2002; 158 (3): 519–528. doi: https://doi.org/10.1083/jcb.200201106
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