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)

Methionine enkephalin, the endogenous opioid peptide, has a diversity of effects on the immune system. Although the biological effects of the pentapeptide have been well documented, little is known about the intracellular events involved in the effects of opioids on human immunodeficiency virus (HIV) infected immune cells. In the present investigation, the possible mechanism of apoptosis alleviated by exposure of methionine enkephalin at 1 micromol/l to CEM x 174 cells, the hybrid lymphocytes, infected with simian immunodeficiency virus (SIV) in vitro is elucidated. Apoptosis and cell cycle analysis is carried out by flow cytometry, the phosphorylation of mitogen-activated protein kinases (MAPK) ERK1 and ERK2 is detected by Western blotting assay, and changes of calcium concentration were analyzed using the calcium-sensitive dye Fluo-3 AM. The results exhibit that methionine enkephalin at the concentrations of 1 micromol/l increase remarkably the proportion of vital cells and decrease the apoptotic cells based on annexin V binding assay. In response to the treatment with methionine enkephalin, SIV-infected cells display a prolonged survival and are accumulated in G1 phase. Methionine enkephalin increase obviously the content of intracellular calcium in normal cells within 1-2 min and maintains a high level within monitoring time. However, the intracellular calcium reaches the highest level at 1 min and subsequently decline to background in SIV infected group. In addition, methionine enkephalin also elevates the levels of protein kinase C (PKC) activity and phosphorylated extracellular signal-regulated kinase (ERK) 1/2. It is proposed that calcium-PKC-MAPK cascade is involved in methionine enkephalin-prolonged survival of SIV-infected cells in the early stages of virus infection. The results provide a further evidence for potential use of methionine enkephalin on the therapy of Acquired Immunodeficiency Syndrome (AIDS).
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PMID:Signaling pathway involved in methionine enkephalin-promoted survival of lymphocytes infected by simian immunodeficiency virus in the early stage in vitro. 1497 62

To determine whether Insulin-like growth factor (IGF-I) treatment represents a potential means of enhancing the survival of cardiac muscle cells from adriamycin (ADR)-induced cell death, the present study examined the ability of IGF-I to prevent cell death. The study was performed utilising the embryonic, rat, cardiac muscle cell line, H9C2. Incubating cardiac muscle cells in the presence of adriamycin increased cell death, as determined by MTT assay and annexin V-positive cell number. The addition of 100 ng/mL IGF-I, in the presence of adriamycin, decreased apoptosis. The effect of IGF-I on phosphorylation of PI, a substrate of phosphatidylinositol 3-kinase (PI 3-kinase) or protein kinase B (AKT), was also examined in H9C2 cardiac muscle cells. IGF-I increased the phosphorylation of ERK 1 and 2 and PKC zeta kinase. The use of inhibitors of PI 3-kinase (LY 294002), in the cell death assay, demonstrated partial abrogation of the protective effect of IGF-I. The MEK1 inhibitor-PD098059 and the PKC inhibitor-chelerythrine exhibited no effect on IGF-1-induced cell protection. In the regulatory subunit of PI3K-p85- dominant, negative plasmid-transfected cells, the IGF-1-induced protective effect was reversed. This data demonstrates that IGF-I protects cardiac muscle cells from ADR-induced cell death. Although IGF-I activates several signaling pathways that contribute to its protective effect in other cell types, only activation of PI 3-kinase contributes to this effect in H9C2 cardiac muscle cells.
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PMID:Signal transduction of the protective effect of insulin like growth factor-1 on adriamycin-induced apoptosis in cardiac muscle cells. 1508 39

CD43 down-regulation during the apoptosis of PMN (polymorphonuclear cells) is not caused by proteolysis or internalization. Could it be released with bleb-derived membrane vesicles? Membrane blebbing was followed by microscopy on PMN 'synchronized' by an overnight incubation at 15 degrees C before their spontaneous apoptosis at 37 degrees C. Released vesicles were quantified by flow cytometry. Membrane blebbing, release of bleb-derived membrane vesicles, decrease of CD43/CD16 expression and phosphatidylserine externalization occurred simultaneously. However, caspase and PKC inhibition prevented annexin binding but not blebbing, vesicle release or CD43 expression decrease; myosin light chain kinase inhibition prevented cell blebbing and vesicle release but had no effect on CD43/CD16 down-regulation or annexin V binding. By electron microscopy, CD43 appeared poorly expressed on membrane blebs and concentrated at bleb 'necks'. In conclusion, CD43 down-regulation is not caused by cell blebbing. Cell blebbing, phospholipid 'flip-flop' and CD43/CD16 down-regulation are independent membrane events.
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PMID:Early membrane events in polymorphonuclear cell (PMN) apoptosis: membrane blebbing and vesicle release, CD43 and CD16 down-regulation and phosphatidylserine externalization. 1515 65

Src is a non-receptor protein tyrosine kinase that transduces signals regulating cell growth and differentiation. We report here that activation of signaling pathway after blockade of tyrosine phosphorylation by PP2 (4-amino-5-(4-chloro-phenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine), a potent and selective inhibitor of the Src-family tyrosine kinase, can lead to cell death in murine B cell leukemia, 70Z/3. Death from PP2 occurred by apoptosis as indicated by the induction of caspase activation and annexin V/propidium iodide staining. Interestingly, PP2 was found to be able to enhance the DNA binding activity of nuclear factor kappaB (NF-kappaB) before induction of apoptosis without accompanying by increased phosphorylation of inhibitor of NF-kappaB-alpha (IkappaB-alpha). Additionally, immunoblotting analysis with PP2-treated cell extract demonstrated that, compared to other protein kinase C (PKC) isotypes, the translocation of novel PKC isotypes from the cytosol to membrane fraction was sustained for a longer time. These data suggest that the inhibition of Src-mediated tyrosine phosphorylation by PP2 may tilt the balance between each PKC isotypes, which in turn, activate NF-kappaB transcription factor, leading to apoptosis.
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PMID:Apoptotic effect of PP2 a Src tyrosine kinase inhibitor, in murine B cell leukemia. 1537 99

The effect of inhibition of mitogen and stress-activated protein kinases 1/2 (MSK1/2) on lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophage cells was investigated. Pretreatment with Ro 31-8220, an inhibitor of MSK1/2, induced cell death in LPS-stimulated RAW 264.7 cells. In contrast, calphostin C, another inhibitor of protein kinase C, did not cause cell death. Cell death was not mediated by the release of pro-inflammatory mediators from LPS-stimulated RAW 264.7 cells. Cell death was accompanied by DNA fragmentation and annexin V binding, suggesting apoptotic cell death. Further, several caspase inhibitors did not prevent LPS-induced cell death of Ro 31-8220-pretreated RAW 264.7 cells. Nuclear translocation of apoptosis-inducing factor (AIF) was detected in Ro 31-8220-pretreated cells after LPS stimulation. Cell death was due to mitochondrial damage. Ro 31-8220 exclusively inhibited the phosphorylation of cAMP-responsive element binding protein (CREB), a substrate of MSK1/2. RAW 264.7 cells transfected with the dominant-negative MSK1 clones underwent cell death in response to LPS. Hence, it was suggested that MSK1/2 might play a critical role in the survival of LPS-stimulated RAW 264.7 cells.
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PMID:A role of mitogen and stress-activated protein kinase 1/2 in survival of lipopolysaccharide-stimulated RAW 264.7 macrophages. 1568 Nov 59

Apoptosis of terminally differentiated chondrocytes allows the replacement of growth plate cartilage by bone. Despite its importance, little is known about the regulation of chondrocyte apoptosis. We show that overexpression of annexin V, which binds to the cytoplasmic domain of beta5 integrin and protein kinase C alpha (PKCalpha), stimulates apoptotic events in hypertrophic growth plate chondrocytes. To determine whether the balance between the interactions of annexin V/beta5 integrin and annexin V/active PKCalpha play a role in the regulation of terminally differentiated growth plate chondrocyte apoptosis, a peptide mimic of annexin V (Penetratin (Pen)-VVISYSMPD) that binds to beta5 integrin but not to PKCalpha was used. This peptide stimulated apoptotic events in growth plate chondrocytes. Suppression of annexin V expression using small interfering ribonucleic acid decreased caspase-3 activity and increased cell viability in Pen-VVISYSMPD-treated growth plate chondrocytes. An activator of PKC resulted in a further decrease of cell viability and further increase of caspase-3 activity in Pen-VVISYSMPD-treated growth plate chondrocytes, whereas inhibitors of PKCalpha led to an increase of cell viability and decrease of caspase-3 activity of Pen-VVISYSMPD-treated cells. These findings suggest that binding of annexin V to active PKCalpha stimulates apoptotic events in growth plate chondrocytes and that binding of annexin Vto beta5 integrin controls these interactions and ultimately apoptosis.
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PMID:Annexin V/beta5 integrin interactions regulate apoptosis of growth plate chondrocytes. 1691 49

Mitogen-activated protein kinase (MAPK) and protein kinase C (PKC) are activated in the majority of gliomas and contribute to tumor cell growth and survival. Sorafenib (Bay43-9006; Nexavar) is a dual-action Raf and vascular endothelial growth factor receptor inhibitor that blocks receptor phosphorylation and MAPK-mediated signaling and inhibits growth in a number of tumor types. Because our initial studies of this agent in a series of glioma cell lines showed only partial growth inhibition at clinically achievable concentrations, we questioned whether inhibition of PKC signaling using the PKC-delta inhibitor rottlerin might potentiate therapeutic efficacy. Proliferation assays, apoptosis induction studies, and Western immunoblot analysis were conducted in cells treated with sorafenib and rottlerin as single agents or in combination. Sorafenib and rottlerin reduced proliferation in all cell lines when used as single agents, and the combination produced marked potentiation of growth inhibition. Flow-cytometric measurements of cells stained with Annexin V-propidium iodide and immunocytochemical assessment of cytochrome c and apoptosis-inducing factor release demonstrated that addition of rottlerin resulted in significantly higher levels of apoptosis than sorafenib alone. In addition, the combination of sorafenib and rottlerin reduced or completely inhibited the phosphorylation of extracellular signal-regulated kinase and Akt and down-regulated cell cycle regulatory proteins such as cyclin-D1, cyclin-D3, cyclin-dependent kinase (cdk)4, and cdk6 in a dose- and time-dependent manner. Our results clearly indicate that inhibition of PKC-delta signaling enhances the antiproliferative effect of sorafenib in malignant human glioma cell lines and support the examination of combinations of signaling inhibitors in these tumors.
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PMID:Coadministration of sorafenib with rottlerin potently inhibits cell proliferation and migration in human malignant glioma cells. 1695 60

Visceral leishmaniasis (VL) produced in BALB/c mice through intracardial administration of Leishmania donovani amastigotes was accompanied by hepatosplenomegaly with high organ parasite load and lymphadenopathy when followed up to 4-months or so. To elucidate the mechanism of immunosuppression associated with VL, we report here progressive impairment of the proliferative response of lymph node cells (lymphocytes) from infected animals (I-LNC) to in vitro stimulation with the combination of phorbol 12-myristate 13-acetate (PMA) and ionomycin (Io) that could be related to the downregulation of PKC and MAP kinase (ERK 1/2) activation process. Further, pretreatment of I-LNC with the protein phosphatase inhibitor okadaic acid (OA), but not with calyculin A or sodium orthovanadate, significantly restored their proliferative response as well as PMA-induced activation of PKC. A population of LNC (primarily T-lymphocytes) from chronically infected animals was shown to undergo apoptosis, the number of which increased considerably following PMA+ Io stimulation. The apoptotic pathway, which was followed through binding of cells to Annexin V, activation of caspase-3 and fragmentation of DNA, involved destabilization of mitochondria, probably as a result of downregulation of PKC and Bcl-2. Interestingly, prior incubation of I-LNC with OA reversed the state of cell cycle arrest (anergy) and apoptosis through progression of cells from G0/G1 to S and G2/M phases with transcriptional activation of IL-2 and IL-2R genes. Our results suggest that the cellular (immune) dysfunction in VL could be attributed to dephosphorylation of key molecules in the T-lymphocyte signaling pathway by Ser/Thr phosphatase leading to their inactivation.
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PMID:Lymph node cells from BALB/c mice with chronic visceral leishmaniasis exhibiting cellular anergy and apoptosis: involvement of Ser/Thr phosphatase. 1701 55

There is substantial interest in identifying agents that differentially activate keratinocyte differentiation versus apoptosis. Okadaic acid (OA) is a tumor promoter in mouse skin that also stimulates apoptosis of murine keratinocytes. OA also enhances human keratinocyte differentiation; however, the impact of OA treatment on apoptosis in these cells has not been examined. We show that OA promotes normal human keratinocyte apoptosis as evidenced by increased accumulation of cells having sub-G1/S DNA content, decreased mitochondrial integrity, increased annexin V binding, increased cytoplasmic cytochrome c level, and increased procaspase 3 and PARP cleavage. Cyclin A, cyclin D1, cdk2, cdk4, p53 and p21 levels are reduced. These changes are associated with release of the PKCdelta catalytic domain and increased phosphorylation of PKCdelta-T(505)-responses consistent with PKCdelta activation. In contrast, phosphorylation of PKCdelta-Y(311) is not increased. The apoptotic response is enhanced in OA treated cells in the presence of p38delta, a PKCdelta target. OA treatment selectively activated p38delta, and OA-dependent apoptosis is not inhibited by treatment with the p38alpha/beta inhibitor, SB203580. These findings are consistent with the idea that the response is mediated by p38delta. Our data indicate that OA is an agent that regulates both keratinocyte differentiation and apoptosis, and that this regulation is mediated via activation of a PKCdelta/p38delta signaling cascade.
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PMID:Activation of PKCdelta and p38delta MAPK during okadaic acid dependent keratinocyte apoptosis. 1725 48

Suicidal death of erythrocytes or eryptosis is characterized by cell shrinkage and cell membrane scrambling leading to phosphatidylserine exposure at the erythrocyte surface. The cell membrane scrambling is triggered by an increase in cytosolic Ca(2+) activity and activation of protein kinase C (PKC). Phosphatidylserine exposure fosters adherence of affected erythrocytes to the vascular wall. Thus, microcirculation in ischemic tissues may be impaired by the appearance of eryptotic erythrocytes. Ischemia leads to release of adenosine, which in most tissues leads to vasodilation and protects against cell injury. The present experiments explored whether adenosine influences mechanisms underlying eryptosis. Erythrocyte phosphatidylserine exposure was estimated from annexin V binding, cell volume from forward scatter and cytosolic Ca(2+) activity from Fluo3 fluorescence. Glucose depletion (for 24 or 48 h) significantly increased annexin binding and decreased forward scatter, effects partially reversed by adenosine. The protective effect of adenosine reached statistical significance (s.d.) at > =30 microM. Low Cl(-) solution (Cl(-) exchanged by gluconate for 24 h) similarly increased annexin binding and decreased forward scatter, effects again reversed by adenosine (s.d. at > or =10 and 30 microM, respectively). Similarly, phosphatase inhibitor okadaic acid (OA, 1 microM) and PKC activator phorbol 12-myristate-13-acetate (PMA, 3 microM) significantly enhanced annexin binding and decreased forward scatter. Adenosine significantly blunted the effects of OA and PMA on annexin V binding (s.d. at > or =30 and 10 microM, respectively) and the effect of OA on forward scatter (s.d. at > or =10 microM). In conclusion, adenosine inhibits eryptosis by a mechanism presumably effective downstream of PKC. The effect may participate in the maintenance of microcirculation in ischemic tissue.
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PMID:Adenosine protects against suicidal erythrocyte death. 1728 97


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