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Originally published In Press as doi:10.1074/jbc.M305352200 on June 20, 2003
J. Biol. Chem., Vol. 278, Issue 35, 33011-33019, August 29, 2003
Overexpression of Interferon- -inducible GTPase Inhibits Coxsackievirus B3-induced Apoptosis through the Activation of the Phosphatidylinositol 3-Kinase/Akt Pathway and Inhibition of Viral Replication*
Huifang M. Zhang,
Ji Yuan,
Paul Cheung  ,
Honglin Luo,
Bobby Yanagawa  ,
David Chau,
Najwan Stephan-Tozy,
Brian W. Wong,
Jingchun Zhang,
Janet E. Wilson,
Bruce M. McManus and
Decheng Yang ¶
From the
Department of Pathology and Laboratory Medicine, University of British
Columbia-MRL/The iCAPTUR4E Centre, St. Paul's Hospital, Vancouver,
British Columbia V6Z 1Y6, Canada
Our previous studies using differential mRNA display have shown that
interferon- -inducible GTPase (IGTP), was up-regulated in coxsackievirus
B3 (CVB3)-infected mouse hearts. In order to explore the effect of IGTP
expression on CVB3-induced pathogenesis, we have established a
doxycycline-inducible Tet-On HeLa cell line overexpressing IGTP and have
analyzed activation of several signaling molecules that are involved in cell
survival and death pathways. We found that following IGTP overexpression,
protein kinase B/Akt was strongly activated through phosphorylation, which
leads to phosphorylation of glycogen synthase kinase-3 (GSK-3). Furthermore,
in the presence of CVB3 infection, the intensity of the phosphorylation of Akt
was further enhanced and associated with a delayed activation of caspase-9 and
caspase-3. These data indicate that IGTP expression appears to confer cell
survival in CVB3-infected cells, which was confirmed by
3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium
salt cell viability assay. However, the ability of IGTP to induce
phosphorylation of Akt and to promote cell survival was attenuated by the
phosphotidylinositol-3 kinase (PI3-K) inhibitor LY294002. Transient
transfection of the cells with a dominant negative Akt construct followed by
doxycycline induction and CVB3 infection reversed Akt phosphorylation to basal
levels and returned caspase-3 activity to levels similar to those when the
PI3-K inhibitor LY294002 was added. Moreover, IGTP expression inhibited viral
replication and delayed CVB3-induced cleavage of eukaryotic translation
initiation factor 4G, indicating that IGTP-mediated cell survival relies on
not only the activation of PI3-K/Akt, inactivation of GSK-3 and suppression of
caspase-9 and caspase-3 but also the inhibition of viral replication.
Received for publication, May 21, 2003
* This work was supported in part by grants from the Heart and Stroke
Foundation of British Columbia and Yukon and the Canadian Institutes of Health
Research (to D. C. Y. and B. M.McM.). The costs of publication of this article
were defrayed in part by the payment of page charges. This article must
therefore be hereby marked "advertisement" in accordance
with 18 U.S.C. Section 1734 solely to indicate this fact.
 Supported by a studentship from the Heart and Stroke Foundation of British
Columbia and Yukon.
 Supported by a studentship from the Canadian Institutes of Health
Research.
¶
To whom correspondence should be addressed: Cardiovascular Research
Laboratory, University of British Columbia, St. Paul's Hospital, 1081 Burrard
St., Vancouver, British Columbia V6Z 1Y6, Canada. Tel.: 604-682-2344 (ext.
62872); Fax: 604-806-8351; E-mail:
dyang{at}mrl.ubc.ca.
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Copyright © 2003 by the American Society for Biochemistry and Molecular Biology.
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