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*
Department of Pharmacology, University of Illinois, Chicago, IL 60612;
Friedrich Miescher Institute, Basel, Switzerland;
Howard Hughes Medical Institute, South Los Angeles, CA 90095;
Division of Signal Transduction, Beth Israel Deaconess Medical Center and Department of Cell Biology, Harvard Medical School, Boston, MA 02215; and
¶ Department of Molecular Microbiology and Immunology, St. Louis University, St. Louis, MO 63104
The Janus kinase/STAT pathway has emerged as the paradigm of
IFN-induced protection from viral infections. However, the possible
participation of other signaling proteins in this protection is not
clearly understood. In this report, we demonstrate that activation of
phosphatidylinositol 3-kinase (PI3K) by either serum factors or IFNs
blocks cell death induced by encephalomyocarditis virus (EMCV) and HSV.
This increased resistance to virus-induced cell death does not involve
the activation of the STAT pathway and occurs in the presence of normal
viral replication. Interestingly, the cell uses two different PI3K
regulated pathways to block EMCV- and HSV-induced cell death. The
increased sensitivity of p85
-/- embryonic fibroblasts
to EMCV-induced cell death is specifically corrected by overexpression
of an activated allele of Akt/protein kinase B, but not
activated mitogen-activated protein kinase extracellular kinase.
Conversely, the augmented sensitivity of p85-/- cells
to HSV-induced cell death was compensated for by expression of an
activated form of mitogen-activated protein kinase extracellular
kinase, but not by activated Akt/protein kinase B. We conclude from
these data that PI3K-activated pathways function in parallel with the
Janus kinase/STAT pathway to protect cells from the lethal effects of
viruses.
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