title: The localization of protein kinase Cdelta in different subcellular sites affects its proapoptotic and antiapoptotic functions and the activation of distinct downstream signaling pathways.
abstract: Protein kinase Cdelta (PKCdelta) regulates cell apoptosis and survival in diverse cellular systems. PKCdelta 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 PKCdelta constitutively active mutant targeted to the cytosol, nucleus, mitochondria, and endoplasmic reticulum (ER) and examined whether the subcellular localization of PKCdelta affects its apoptotic and survival functions. PKCdelta-Cyto, PKCdelta-Mito, and PKCdelta-Nuc induced cell apoptosis, whereas no apoptosis was observed with the PKCdelta-ER. PKCdelta-Cyto and PKCdelta-Mito underwent cleavage, whereas no cleavage was observed in the PKCdelta-Nuc and PKCdelta-ER. Similarly, caspase-3 activity was increased in cells overexpressing PKCdelta-Cyto and PKCdelta-Mito. In contrast to the apoptotic effects of the PKCdelta-Cyto, PKCdelta-Mito, and PKCdelta-Nuc, the PKCdelta-ER protected the cells from tumor necrosis factor-related apoptosis-inducing ligand-induced and etoposide-induced apoptosis. Moreover, overexpression of a PKCdelta kinase-dead mutant targeted to the ER abrogated the protective effect of the endogenous PKCdelta and increased tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis. The localization of PKCdelta differentially affected the activation of downstream signaling pathways. PKCdelta-Cyto increased the phosphorylation of p38 and decreased the phosphorylation of AKT and the expression of X-linked inhibitor of apoptosis protein, whereas PKCdelta-Nuc increased c-Jun NH(2)-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 PKCdelta-Cyto, whereas c-Jun NH(2)-terminal kinase activation mediated the apoptotic effect of PKCdelta-Nuc. Our results indicate that the subcellular localization of PKCdelta plays important roles in its proapoptotic and antiapoptotic functions and in the activation of downstream signaling pathways.
authors.affiliation: Hermelin Brain Tumor Center, Department of Neurosurgery, Henry Ford Hospital, Detroit, MI 48202, USA.
authors.forename: Ruth
authors.initials: R
authors.lastname: Gomel
authors.forename: Cunli
authors.initials: C
authors.lastname: Xiang
authors.forename: Susan
authors.initials: S
authors.lastname: Finniss
authors.forename: Hae Kyung
authors.initials: HK
authors.lastname: Lee
authors.forename: Wei
authors.initials: W
authors.lastname: Lu
authors.forename: Hana
authors.initials: H
authors.lastname: Okhrimenko
authors.forename: Chaya
authors.initials: C
authors.lastname: Brodie
mesh_terms: D017209:Apoptosis; D001932:Brain Neoplasms / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005910:Glioma / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D010766:Phosphorylation; D051745:Protein Kinase C-delta / Q000096:biosynthesis*; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D051745:Protein Kinase C-delta; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases