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Signaling and Regulation

The Localization of Protein Kinase C in Different Subcellular Sites Affects Its Proapoptotic and Antiapoptotic Functions and the Activation of Distinct Downstream Signaling Pathways

Hermelin Brain Tumor Center, Department of Neurosurgery, Henry Ford Hospital, Detroit, Michigan

Requests for reprints: Chaya Brodie, Hermelin Brain Tumor Center, Department of Neurosurgery, Henry Ford Hospital, Detroit, MI 48202. Phone: 313-916-8619; Fax: 313-916-9855. E-mail: chaya{at}brodienet.com

Protein kinase C (PKC) regulates cell apoptosis and survival in diverse cellular systems. PKC translocates to different subcellular sites in response to apoptotic stimuli; however, the role of its subcellular localization in its proapoptotic and antiapoptotic functions is just beginning to be understood. Here, we used a PKC constitutively active mutant targeted to the cytosol, nucleus, mitochondria, and endoplasmic reticulum (ER) and examined whether the subcellular localization of PKC affects its apoptotic and survival functions. PKC-Cyto, PKC-Mito, and PKC-Nuc induced cell apoptosis, whereas no apoptosis was observed with the PKC-ER. PKC-Cyto and PKC-Mito underwent cleavage, whereas no cleavage was observed in the PKC-Nuc and PKC-ER. Similarly, caspase-3 activity was increased in cells overexpressing PKC-Cyto and PKC-Mito. In contrast to the apoptotic effects of the PKC-Cyto, PKC-Mito, and PKC-Nuc, the PKC-ER protected the cells from tumor necrosis factor–related apoptosis-inducing ligand–induced and etoposide-induced apoptosis. Moreover, overexpression of a PKC kinase-dead mutant targeted to the ER abrogated the protective effect of the endogenous PKC and increased tumor necrosis factor–related apoptosis-inducing ligand–induced apoptosis. The localization of PKC differentially affected the activation of downstream signaling pathways. PKC-Cyto increased the phosphorylation of p38 and decreased the phosphorylation of AKT and the expression of X-linked inhibitor of apoptosis protein, whereas PKC-Nuc increased c-Jun NH₂-terminal kinase phosphorylation. Moreover, p38 phosphorylation and the decrease in X-linked inhibitor of apoptosis protein expression played a role in the apoptotic effect of PKC-Cyto, whereas c-Jun NH₂-terminal kinase activation mediated the apoptotic effect of PKC-Nuc. Our results indicate that the subcellular localization of PKC plays important roles in its proapoptotic and antiapoptotic functions and in the activation of downstream signaling pathways. (Mol Cancer Res 2007;5(6):627–39)