Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Signaling through the B cell receptor (BCR) of normal splenic B cells, as well as B cell lymphoma lines, can abrogate Fas-mediated apoptosis. Using the B lymphoma line A20.2J, BCR signaling immediately inhibited Fas-induced apoptosis upstream of caspase-8 activation, as determined by Ile-Glu-Thr-Asp-(IETD)ase activity and cleavage of the caspase-8 substrate Bid. Furthermore, following overexpression of a human Fas:FLICE construct, which directly induces caspase activation in a death-inducing signaling complex-independent manner, cells could not be protected through BCR stimulation.Co-incubation with cycloheximide partially reversed protection from apoptosis and increased Fas-stimulated initiator and effector caspase activation, suggesting new protein synthesis is necessary to induce protection upstream of caspase activation. Furthermore, co-incubation with a broad-spectrum protein kinase C (PKC) inhibitor, such as bisindolylmaleimide (Bis), also partially reversed protection from apoptosis, and examination of a panel of PKC inhibitors suggested a role for atypical isozymes in protection. Bis also acted to increase initiator and effector caspase activation upon anti-IgG and anti-Fas treatment. These data suggest that BCR-induced protection is being mediated upstream of initiator caspase activation, and is partially dependent upon both PKC family members and new protein synthesis.
 ...
PMID:B cell receptor signaling mediates immediate protection from Fas-induced apoptosis upstream of caspase activation through an atypical protein kinase C isozyme and de novo protein synthesis. 1293 25

Hypoxia/reoxygenation causes cell death, yet the underlying regulatory mechanisms remain partially understood. Recent studies demonstrate that hypoxia/reoxygenation can activate death receptor and mitochondria-dependent apoptotic pathways, involving Bid and Bax mitochondrial translocation and cytochrome c release. Using mouse lung endothelial cells (MLEC), we examined the role of FLIP, an inhibitor of caspase 8, in hypoxia/reoxygenation-induced cell death. FLIP protected MLEC against hypoxia/reoxygenation by blocking both caspase 8/Bid and Bax/mitochondrial apoptotic pathways. FLIP inhibited Bax activation in wild-type and Bid(-/-) MLEC, indicating independence from the caspase 8/Bid pathway. FLIP also inhibited the expression and activation of protein kinase C (PKC) (alpha, zeta) during hypoxia/reoxygenation and promoted an association of inactive forms of PKC with Bax. Surprisingly, FLIP expression also inhibited death-inducing signal complex (DISC) formation in the plasma membrane and promoted the accumulation of the DISC in the Golgi apparatus. FLIP expression also upregulated Bcl-X(L), an antiapoptotic protein. In conclusion, FLIP decreased DISC formation in the plasma membrane by blocking its translocation from the Golgi apparatus and inhibited Bax activation through a novel PKC-dependent mechanism. The inhibitory effects of FLIP on Bax activation and plasma membrane DISC formation may play significant roles in protecting endothelial cells from the lethal effects of hypoxia/reoxygenation.
 ...
PMID:FLIP protects against hypoxia/reoxygenation-induced endothelial cell apoptosis by inhibiting Bax activation. 1589 75

Depletion of mitochondrial DNA (mtDNA) or treatment with mitochondrial poison CCCP initiates mitochondrial stress signaling, which operates through altered Ca2+ homeostasis. In C2C12 rhabdomyoblasts and A549 human lung carcinoma cells mitochondrial stress signaling activates calcineurin and a number of Ca2+ responsive factors including ATF, NFAT, CEBP/delta and CREB. Additionally, PKC and MAP kinase are also activated. A number of nuclear gene targets including those involved in Ca2+ storage/release (RyR1, calreticulin, calsequestrin), glucose metabolism (hexokinase, pyruvate kinase, Glut4), oncogenesis (TGFbeta1, cathepsin L, IGFR1, melanoma antigen) and apoptosis (Bcl-2, Bid, Bad, p53) are upregulated. Mitochondrial stress in both C2C12 myoblasts and A549 cells induced morphological changes and invasive phenotypes. These cells also showed markedly increased resistance to etoposide-induced apoptosis that is a hallmark of highly invasive tumors. Our results describe a new mechanism of altered nuclear gene expression and phenotypic changes triggered by mitochondrial dysfunction and mtDNA damage.
 ...
PMID:Mitochondria-to-nucleus stress signaling in mammalian cells: nature of nuclear gene targets, transcription regulation, and induced resistance to apoptosis. 1597 49

In this study, we examined the role of protein kinase C (PKC)-epsilon in the apoptosis and survival of glioma cells using tumor necrosis factor-related apoptosis inducing ligand (TRAIL)-stimulated cells and silencing of PKCepsilon expression. Treatment of glioma cells with TRAIL induced activation, caspase-dependent cleavage, and down-regulation of PKCepsilon within 3 to 5 hours of treatment. Overexpression of PKCepsilon inhibited the apoptosis induced by TRAIL, acting downstream of caspase 8 and upstream of Bid cleavage and cytochrome c release from the mitochondria. A caspase-resistant PKCepsilon mutant (D383A) was more protective than PKCepsilon, suggesting that both the cleavage of PKCepsilon and its down-regulation contributed to the apoptotic effect of TRAIL. To further study the role of PKCepsilon in glioma cell apoptosis, we employed short interfering RNAs directed against the mRNA of PKCepsilon and found that silencing of PKCepsilon expression induced apoptosis of various glioma cell lines and primary glioma cultures. To delineate the molecular mechanisms involved in the apoptosis induced by silencing of PKCepsilon, we examined the expression and phosphorylation of various apoptosis-related proteins. We found that knockdown of PKCepsilon did not affect the expression of Bcl2 and Bax or the phosphorylation and expression of Erk1/2, c-Jun-NH2-kinase, p38, or STAT, whereas it selectively reduced the expression of AKT. Similarly, TRAIL reduced the expression of AKT in glioma cells and this decrease was abolished in cells overexpressing PKCepsilon. Our results suggest that the cleavage of PKCepsilon and its down-regulation play important roles in the apoptotic effect of TRAIL. Moreover, PKCepsilon regulates AKT expression and is essential for the survival of glioma cells.
 ...
PMID:Protein kinase C-epsilon regulates the apoptosis and survival of glioma cells. 1610 81

Breast cancer cells often show increased activity of the mitogen-activated protein kinase (MAPK) pathway. We report here that this pathway reduces their sensitivity to death ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and present the underlying mechanism. Activation of protein kinase C (PKC) inhibited TRAIL-induced apoptosis in a protein synthesis-independent manner. Deliberate activation of MAPK was also inhibitory. In digitonin-permeabilized cells, PKC activation interfered with the capacity of recombinant truncated (t)Bid to release cytochrome c from mitochondria. MAPK activation did not affect TRAIL or tumor necrosis factor (TNF)alpha-induced Bid cleavage. However, it did inhibit translocation of (t)Bid to mitochondria as determined both by subcellular fractionation analysis and confocal microscopy. Steady state tBid mitochondrial localization was prohibited by activation of the MAPK pathway, also when the Bcl-2 homology domain 3 (BH3) domain of tBid was disrupted. We conclude that the MAPK pathway inhibits TRAIL-induced apoptosis in MCF-7 cells by prohibiting anchoring of tBid to the mitochondrial membrane. This anchoring is independent of its interaction with resident Bcl-2 family members.
 ...
PMID:The mitogen-activated protein kinase pathway can inhibit TRAIL-induced apoptosis by prohibiting association of truncated Bid with mitochondria. 1648 30

A functional immune system not only requires rapid expansion of antigenic specific T cells, but also requires efficient deletion of clonally expanded T cells to avoid accumulation of T cells. Fas/Fas ligand (FasL)-mediated apoptosis plays a critical role in the deletion of activated peripheral T cells, which is clearly demonstrated by superantigen-induced expansion and subsequent deletion of T cells. In this study, we show that in the absence of protein kinase C-theta (PKC-theta), superantigen (staphylococcal enterotoxin B)-induced deletion of Vbeta8(+) CD4(+) T cells was defective in PKC-theta(-/-) mice. In response to staphylococcal enterotoxin B challenge, up-regulation of FasL, but not Fas, was significantly reduced in PKC-theta(-/-) mice. PKC-theta is thus required for maximum up-regulation of FasL in vivo. We further show that stimulation of FasL expression depends on PKC-theta-mediated activation of NF-AT pathway. In addition, PKC-theta(-/-) T cells displayed resistance to Fas-mediated apoptosis as well as activation-induced cell death (AICD). In the absence of PKC-theta, Fas-induced activation of apoptotic molecules such as caspase-8, caspase-3, and Bid was not efficient. However, AICD as well as Fas-mediated apoptosis of PKC-theta(-/-) T cells were restored in the presence of high concentration of IL-2, a critical factor required for potentiating T cells for AICD. PKC-theta is thus required for promoting FasL expression and for potentiating Fas-mediated apoptosis.
 ...
PMID:The critical role of protein kinase C-theta in Fas/Fas ligand-mediated apoptosis. 1718 68

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent as it selectively kills tumor cells but spares normal cells. Resistance to TRAIL by tumor cells limits its therapeutic use. We have previously shown that protein kinase C-epsilon (PKCepsilon) acts as an antiapoptotic protein in MCF-7 breast cancer cells. In the present study, we have investigated the mechanism(s) by which PKCepsilon contributes to TRAIL resistance. Overexpression of PKCepsilon inhibited caspase-8 and -9 activation, release of mitochondrial cytochrome c and cell death induced by TRAIL, but did not interfere with the recruitment of caspase-8 to the death-inducing signaling complex. Knockdown/inhibition of PKCepsilon resulted in enhanced sensitivity to TRAIL. The level of Bcl-2 was increased and Bid was decreased by PKCepsilon at both the protein and mRNA level but PKCepsilon had no effect on Bax. Knockdown of Bcl-2 by siRNA reversed TRAIL resistance in PKCepsilon-overexpressing cells, whereas depletion of Bid contributed to TRAIL resistance in MCF-7 cells. A decrease in Bid content was also associated with inhibition of TRAIL-induced caspase-8 activation. Furthermore, PKCepsilon depletion or overexpression of DN-PKCepsilon was associated with a decrease in Bcl-2 protein level. Thus, our results suggest that PKCepsilon acts upstream of mitochondria and mediates TRAIL resistance via both Bcl-2 and Bid in MCF-7 cells.
 ...
PMID:Downregulation of Bid is associated with PKCepsilon-mediated TRAIL resistance. 1718 22

High oxygen tension (hyperoxia) causes pulmonary cell death, involving apoptosis, necrosis, or mixed death phenotypes, though the underlying mechanisms remain unclear. In mouse lung endothelial cells (MLEC) hyperoxia activates both extrinsic (Fas-dependent) and intrinsic (mitochondria-dependent) apoptotic pathways. We examined the hypothesis that FLIP, an inhibitor of caspase-8, can protect endothelial cells against the lethal effects of hyperoxia. Hyperoxia caused the time-dependent downregulation of FLIP in MLEC. Overexpression of FLIP attenuated intracellular reactive oxygen species generation during hyperoxia exposure, by downregulating extracellular-regulated kinase-1/2 activation and p47(phox) expression. FLIP prevented hyperoxia-induced trafficking of the death-inducing signal complex from the Golgi apparatus to the plasma membrane. Furthermore, FLIP blocked the activations of caspase-8/Bid, caspases -3/-9, and inhibited the mitochondrial translocation and activation of Bax, resulting in protection against hyperoxia-induced cell death. Under normoxic conditions, FLIP expression increased the phosphorylation of p38 mitogen-activated protein kinase leading to increased phosphorylation of Bax during hyperoxic stress. Furthermore, FLIP expression markedly inhibited protein kinase C activation and expression of distinct protein kinase C isoforms (alpha, eta, and zeta), and stabilized an interaction of PKC with Bax. In conclusion, FLIP exerted novel inhibitory effects on extrinsic and intrinsic apoptotic pathways, which significantly protected endothelial cells from the lethal effects of hyperoxia.
 ...
PMID:FLIP inhibits endothelial cell apoptosis during hyperoxia by suppressing Bax. 1744 7

Myristoylation is the attachment of the 14-carbon fatty acid myristate to the N-terminal glycine residue of proteins. Typically a co-translational modification, myristoylation of proapoptotic cysteinyl-aspartyl proteases (caspase)-cleaved Bid and PAK2 was also shown to occur post-translationally and is essential for their proper localization and proapoptotic function. Progress in the identification and characterization of myristoylated proteins has been impeded by the long exposure times required to monitor incorporation of radioactive myristate into proteins (typically 1-3 months). Consequently, we developed a nonradioactive detection methodology in which a bio-orthogonal azidomyristate analog is specifically incorporated co- or post-translationally into proteins at N-terminal glycines, chemoselectively ligated to tagged triarylphosphines and detected by Western blotting with short exposure times (seconds to minutes). This represents over a million-fold signal amplification in comparison to using radioactive labeling methods. Using rational prediction analysis to recognize putative internal myristoylation sites in caspase-cleaved proteins combined with our nonradioactive chemical detection method, we identify 5 new post-translationally myristoylatable proteins (PKC epsilon, CD-IC2, Bap31, MST3, and the catalytic subunit of glutamate cysteine ligase). We also demonstrate that 15 proteins undergo post-translational myristoylation in apoptotic Jurkat T cells. This suggests that post-translational myristoylation of caspase-cleaved proteins represents a novel mechanism widely used to regulate cell death.
 ...
PMID:Rapid detection, discovery, and identification of post-translationally myristoylated proteins during apoptosis using a bio-orthogonal azidomyristate analog. 1793 26

Protein kinase C epsilon (PKC epsilon ) acts as an antiapoptotic protein and inhibits tumor necrosis factor-alpha (TNF)-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in MCF-7 breast cancer cells. Members of the TNF receptor superfamily trigger apoptosis independent of the tumor suppressor protein p53, which primarily affects DNA damage-induced apoptosis. We have previously shown that PKC epsilon acts upstream of Akt to inhibit receptor-initiated cell death. Since Akt can regulate p53, we have examined the involvement of p53 in PKC epsilon-mediated TRAIL resistance. Overexpression of PKC epsilon in MCF-7 cells (MCF-7/PKC epsilon ) caused a decrease in p53 and an increase in human homolog of murine double minute 2 (Hdm2) and phospho-Hdm2. Depletion of p53 by siRNA attenuated, whereas depletion of Hdm2 enhanced TRAIL-mediated apoptosis. Knockdown of Akt decreased Hdm2 phosphorylation, increased p53 level and potentiated TRAIL-induced cell death. Depletion of epsilon from MCF-7 cells caused an increase in p53, whereas knockdown of p53 caused a decrease in Bid mRNA. Depletion of Akt from MCF-7/PKC epsilon cells resulted in an increase in p53 and Bid. These results suggest that PKC epsilon mediates TRAIL resistance by Akt-mediated phosphorylation of Hdm2 resulting in suppression of p53 expression and downregulation of Bid in MCF-7 breast cancer cells.
 ...
PMID:Protein kinase C epsilon confers resistance of MCF-7 cells to TRAIL by Akt-dependent activation of Hdm2 and downregulation of p53. 1831 51


<< Previous 1 2 3 Next >>