Journal of Biological Chemistry
Volume 281, Issue 32, 11 August 2006, Pages 22799-22807
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Mechanisms of Signal Transduction
Protein Kinase Cϵ Activates Protein Kinase B/Akt via DNA-PK to Protect against Tumor Necrosis Factor-α-induced Cell Death*

https://doi.org/10.1074/jbc.M603390200Get rights and content
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We have previously shown that protein kinase Cϵ (PKCϵ) protects breast cancer cells from tumor necrosis factor-α (TNF)-induced cell death. In the present study, we have investigated if the antiapoptotic function of PKCϵ is mediated via Akt and the mechanism by which PKCϵ regulates Akt activity. TNF caused a transient increase in Akt phosphorylation at Ser473 in MCF-7 cells. Overexpression of PKCϵ in MCF-7 cells increased TNF-induced Akt phosphorylation at Ser473 resulting in its activation. Knockdown of PKCϵ by small interfering RNA (siRNA) decreased TNF-induced Akt phosphorylation/activation and increased cell death. Introduction of constitutively active Akt protected breast cancer MCF-7 cells from TNF-mediated cell death and partially restored cell survival in PKCϵ-depleted cells. Depletion of Akt in MCF-7 cells abolished the antiapoptotic effect of PKCϵ on TNF-mediated cell death. Akt was constitutively associated with PKCϵ and DNA-dependent protein kinase (DNA-PK), and this association was increased by TNF treatment. Overexpression of PKCϵ enhanced the interaction between Akt and DNA-PK. Knockdown of DNA-PK by siRNA inhibited TNF-induced Akt phosphorylation and the antiapoptotic effect of Akt and PKCϵ. These results suggest that PKCϵ activates Akt via DNA-PK to mediate its antiapoptotic function. Furthermore, we report for the first time that DNA-PK can regulate receptor-initiated apoptosis via Akt.

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This work was supported by Grant CA71727 (to A. B.) from the NCI/National Institutes of Health. 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.