Suppression of Apoptosis in the Protein Kinase Cδ Null Mouse in Vivo

Humphries, Michael; Limesand, Kirsten H.; Schneider, Jonathan C.; Nakayama, Keiichi I.; Anderson, Steven M.; Reyland, Mary E.

doi:10.1074/jbc.m507851200

Cited by 130 publications

(178 citation statements)

References 51 publications

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“…The JNK pathway played a major role in the apoptotic effect of PKCyNuc because inhibition of JNK significantly decreased the apoptotic effect of the PKCy-Nuc. JNK has been implicated in the regulation of cell apoptosis in response to various stimuli (51,52) and has been shown to act downstream of PKCy (16,51,53,54). A role for the nuclear PKCy in the activation of JNK is further supported by recent studies that showed that the nuclear translocation of PKCy by etoposide preceded the activation of JNK in salivary gland acinar cells (30,53).…”

Section: Discussionsupporting

confidence: 48%

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

Gomel

Xiang

Finniss

et al. 2007

Molecular Cancer Research

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Protein kinase CD (PKCD) regulates cell apoptosis and survival in diverse cellular systems. PKCD 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 PKCD constitutively active mutant targeted to the cytosol, nucleus, mitochondria, and endoplasmic reticulum (ER) and examined whether the subcellular localization of PKCD affects its apoptotic and survival functions. PKCD-Cyto, PKCD-Mito, and PKCD-Nuc induced cell apoptosis, whereas no apoptosis was observed with the PKCD-ER. PKCD-Cyto and PKCD-Mito underwent cleavage, whereas no cleavage was observed in the PKCD-Nuc and PKCD-ER. Similarly, caspase-3 activity was increased in cells overexpressing PKCD-Cyto and PKCD-Mito. In contrast to the apoptotic effects of the PKCD-Cyto, PKCD-Mito, and PKCD-Nuc, the PKCD-ER protected the cells from tumor necrosis factor -related apoptosis-inducing ligand -induced and etoposideinduced apoptosis. Moreover, overexpression of a PKCD kinase-dead mutant targeted to the ER abrogated the protective effect of the endogenous PKCD and increased tumor necrosis factor -related apoptosis-inducing ligand -induced apoptosis. The localization of PKCD differentially affected the activation of downstream signaling pathways. PKCD-Cyto increased the phosphorylation of p38 and decreased the phosphorylation of AKT and the expression of X-linked inhibitor of apoptosis protein, whereas PKCD-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 PKCD-Cyto, whereas c-Jun NH 2 -terminal kinase activation mediated the apoptotic effect of PKCD-Nuc. Our results indicate that the subcellular localization of PKCD plays important roles in its proapoptotic and antiapoptotic functions and in the activation of downstream signaling pathways.

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Section: Discussionsupporting

confidence: 48%

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

Gomel

Xiang

Finniss

et al. 2007

Molecular Cancer Research

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“…Furthermore, PKC plays a pivotal role in the genotoxic stress response leading to apoptosis in various cell types (Brodie and Blumberg 2003, Reyland 2007, Yoshida 2007a). In addition, cells derived from PKC -/-mice were shown to be defective in mitochondria-dependent apoptosis (Humphries et al 2006, Leitges et al 2001. These findings thus support our proposition of a pro-genotoxic role for PKC.…”

Section: Pkc and Apoptotic Cell Death Upon Genotoxic Insultssupporting

confidence: 79%

“…For example, PKC activators enhanced caspase activation, whereas an inhibitor of PKC prevented caspase activation in response to DNA damage (Basu et al 2001). In particular, studies with PKC -/-mice suggest that PKC plays pivotal roles in the regulation of cell proliferation and apoptosis (Humphries et al 2006, Leitges et al 2001. PKC is activated by a variety of stimuli including ionizing radiation, anti-cancer agents, reactive oxygen species (ROS), ultraviolet radiation, growth factors and cytokines (Carpenter et al 2002, Chen et al 1999, Denning et al 1996, Konishi et al 2001, Reyland et al 1999, Yoshida and Kufe 2001.…”

Section: Pkc and Apoptotic Cell Death Upon Genotoxic Insultsmentioning

confidence: 99%

Role for PKCδ on Apoptosis in the DNA Damage Response

Yoshida¹

2011

Selected Topics in DNA Repair

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“…Protein kinase Cd may be activated in response to Ara-C as demonstrated in U937 human leukaemia cells (Emoto et al, 1996), cisplatin in H69 human small-cell lung cancer cells (Persaud et al, 2005), and etoposide in human glioma cells (Blass et al, 2002). Interestingly, apoptosis was severely impaired when the PKCd function or expression was inhibited (Humphries et al, 2006). In addition, activation of PKCd may cause G1 and G2 cell cycle arrest through the modulation of cyclin and cyclin-dependent kinase expression (Griner and Kazanietz, 2007).…”

mentioning

confidence: 99%

Antiproliferative activity of PEP005, a novel ingenol angelate that modulates PKC functions, alone and in combination with cytotoxic agents in human colon cancer cells

et al. 2008

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PEP005 is a novel ingenol angelate that modulates protein kinases C (PKC) functions by activating PKCd and inhibiting PKCa. This study assessed the antiproliferative effects of PEP005 alone and in combination with several other anticancer agents in a panel of 10 human cancer cell lines characterised for expression of several PKC isoforms. PEP005 displayed antiproliferative effects at clinically relevant concentrations with a unique cytotoxicity profile that differs from that of most other investigated cytotoxic agents, including staurosporine. In a subset of colon cancer cells, the IC 50 of PEP005 ranged from 0.01 -140 mM. The antiproliferative effects of PEP005 were shown to be concentration-and time-dependent. In Colo205 cells, apoptosis induction was observed at concentrations ranging from 0.03 to 3 mM. Exposure to PEP005 also induced accumulation of cells in the G1 phase of the cell cycle. In addition, PEP005 increased the phosphorylation of PKCd and p38. In Colo205 cells, combinations of PEP005 with several cytotoxic agents including oxaliplatin, SN38, 5FU, gemcitabine, doxorubicin, vinorelbine, and docetaxel yielded sequence-dependent antiproliferative effects. Cell cycle blockage induced by PEP005 in late G1 lasted for up to 24 h and therefore a 24 h lag-time between PEP005 and subsequent exposure to cytotoxics was required to optimise PEP005 combinations with several anticancer agents. These data support further evaluation of PEP005 as an anticancer agent and may help to optimise clinical trials with PEP005-based combinations in patients with solid tumours.

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Suppression of Apoptosis in the Protein Kinase Cδ Null Mouse in Vivo

Abstract: Protein kinase C (PKC)␦

Cited by 130 publications

References 51 publications

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

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

Role for PKCδ on Apoptosis in the DNA Damage Response

Antiproliferative activity of PEP005, a novel ingenol angelate that modulates PKC functions, alone and in combination with cytotoxic agents in human colon cancer cells

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