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

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 co...

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Autores principales: Robert, Amélie, Miron, Marie-Joëlle, Champagne, Claudia, Gingras, Marie-Claude, Branton, Philip E., Lavoie, Josée N.
Formato: Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2002
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2173819/
https://www.ncbi.nlm.nih.gov/pubmed/12163473
http://dx.doi.org/10.1083/jcb.200201106
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author Robert, Amélie
Miron, Marie-Joëlle
Champagne, Claudia
Gingras, Marie-Claude
Branton, Philip E.
Lavoie, Josée N.
author_facet Robert, Amélie
Miron, Marie-Joëlle
Champagne, Claudia
Gingras, Marie-Claude
Branton, Philip E.
Lavoie, Josée N.
author_sort Robert, Amélie
collection PubMed
description 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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spelling pubmed-21738192008-05-01 Distinct cell death pathways triggered by the adenovirus early region 4 ORF 4 protein Robert, Amélie Miron, Marie-Joëlle Champagne, Claudia Gingras, Marie-Claude Branton, Philip E. Lavoie, Josée N. J Cell Biol Article 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. The Rockefeller University Press 2002-08-05 /pmc/articles/PMC2173819/ /pubmed/12163473 http://dx.doi.org/10.1083/jcb.200201106 Text en Copyright © 2002, The Rockefeller University Press This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Article
Robert, Amélie
Miron, Marie-Joëlle
Champagne, Claudia
Gingras, Marie-Claude
Branton, Philip E.
Lavoie, Josée N.
Distinct cell death pathways triggered by the adenovirus early region 4 ORF 4 protein
title Distinct cell death pathways triggered by the adenovirus early region 4 ORF 4 protein
title_full Distinct cell death pathways triggered by the adenovirus early region 4 ORF 4 protein
title_fullStr Distinct cell death pathways triggered by the adenovirus early region 4 ORF 4 protein
title_full_unstemmed Distinct cell death pathways triggered by the adenovirus early region 4 ORF 4 protein
title_short Distinct cell death pathways triggered by the adenovirus early region 4 ORF 4 protein
title_sort distinct cell death pathways triggered by the adenovirus early region 4 orf 4 protein
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2173819/
https://www.ncbi.nlm.nih.gov/pubmed/12163473
http://dx.doi.org/10.1083/jcb.200201106
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