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MBC in Press, published online ahead of print October 17, 2007
Mol. Biol. Cell 10.1091/mbc.E07-04-0358

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Submitted on April 19, 2007
Revised on September 10, 2007
Accepted on October 10, 2007

IFN{alpha} Induces Nucleus-independent Apoptosis by Activating ERK1/2 and JNK Downstream of PI3K and mTOR

Theocharis Panaretakis,*{dagger} Linn Hjortsberg,*{dagger} Katja Pokrovskaja Tamm,* Ann-Charlotte Björklund,* Bertrand Joseph,{ddagger} and Dan Grandér*

*Department of Oncology and Pathology, Cancer Centre Karolinska (CCK) R8:03, Karolinska Hospital and Institute, S-171 76 Stockholm, Sweden; {ddagger}Institute of Environmental Medicine, Division of Toxicology, Karolinska Institutet, S-171 77 Stockholm, Sweden

Monitoring Editor: Gerard Evan

Interferon-alpha (IFN{alpha}) induces apoptosis via Bak and Bax and the mitochondrial pathway. Here we investigated the role of known IFN{alpha}-induced signaling cascades upstream of Bak activation. By pharmacological and genetic inhibition of the kinases PKC{delta}, ERK and JNK in U266–1984- and RHEK-1 cells we could demonstrate that all three enzymes are critical for the apoptosis associated mitochondrial events and apoptotic cell death induced by IFN{alpha}, at a step downstream of PI3K and mTOR. Furthermore, the activation of JNK was found to occur in a PKC{delta}/ERK dependent manner. Inhibition of these kinases did not affect the canonical IFN{alpha}-stimulated JAK-STAT signaling or expression of IFN-responsive genes. Therefore enucleated cells (cytoplasts) were examined for IFN{alpha}-induced apoptosis, to test directly whether this process depends on gene transcription. Cytoplasts were found to undergo apoptosis following IFN{alpha} treatment, as analyzed by several apoptosis markers using flow cytometry, live cell imaging and biochemical analysis of flow-sorted cytoplasts. Furthermore, inhibition of mTOR, ERK and JNK blocked IFN{alpha}-induced apoptosis in cytoplasts. In conclusion, IFN{alpha}-induced apoptosis requires activation of ERK1/2, PKC{delta} and JNK downstream of PI3K and mTOR, and can occur in a nucleus-independent manner, thus demonstrating for the first time that IFN{alpha} induces apoptosis in the absence of de novo transcription.

{dagger}These authors contributed equally to this work.

Address correspondence to: Dan Grandér (Dan.Grander{at}cck.ki.se)






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