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)

The functional role of the cyclin-dependent kinase inhibitor p21(WAF1/CIP1) in leukemic cell G1 arrest, differentiation, and apoptosis induced by two PKC activators (PMA and bryostatin 1) was examined using antisense-expressing lines [U937/p21AS(F4) and U937/p21AS(B8)]. Following incubation with 10 nM PMA (24 h), antisense-expressing cells displayed induction of p27(KIP1) but not of p21, whereas empty vector-containing cells (U937/pREP4) exhibited induction of both p21 and p27. Antisense-expressing cells were impaired in G1 arrest, dephosphorylation of the retinoblastoma protein, dephosphorylation and reduction in activity of cyclin-dependent kinase 2, and acquisition of differentiated features (e.g., plastic adherence). Bryostatin 1 induced p27 but not p21 in control cells and was less effective than PMA in initiating G1 arrest and related events. Nevertheless, disruption of p21 expression abrogated the effects of bryostatin 1 on cell cycle arrest and cellular maturation. Dysregulation of p21 did not, however, modify PMA- or bryostatin 1-mediated down-regulation of c-Myc protein. Unexpectedly, disruption of p21 failed to attenuate the net reduction in viable cell number following PMA or bryostatin 1 treatment inasmuch as impaired differentiation was accompanied by a lowered threshold for PMA- and bryostatin 1-induced apoptosis. Inhibition of p21 expression also promoted PMA- and bryostatin 1-mediated loss of mitochondrial transmembrane potential (DeltaPsim ) and release of cytochrome c into the cytosol. Together, these findings demonstrate a critical functional role for p21 in regulating myelomonocytic leukemic cell G1 arrest and differentiation following exposure to two PKC activators exhibiting disparate patterns of activity. They also suggest that following treatment with these agents, dysregulation of p21 prevents leukemic cells from engaging a normal differentiation program through a c-Myc-independent mechanism, and instead directs cells along an apoptotic pathway.
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PMID:Evidence of a functional role for the cyclin-dependent kinase inhibitor p21(WAF1/CIP1/MDA6) in the reciprocal regulation of PKC activator-induced apoptosis and differentation in human myelomonocytic leukemia cells. 977 Mar 54

In cardiac fibroblasts, angiotensin II (Ang II) induced a rapid increase in extracellular signal regulated kinase (ERK) activity in a pertussis toxin insensitive manner. This ERK activation was abolished by the Gq-associated phospholipase C inhibitor U73122 but was insensitive to protein kinase C (PKC) inhibitors or PKC downregulation by phorbol ester. Intracellular Ca2+ chelation by BAPTA-AM or TMB-8 abolished Ang II induced ERK activation, whereas treatment with EGTA or nifedipine did not affect it. Ca2+ ionophore A23187 also induced a rapid increase in ERK activity to an extent similar to that of Ang II stimulation. Calmodulin inhibitors (W7 and calmidazolium) and tyrosine kinase inhibitors (genistein and ST638) completely blocked ERK activation by Ang II and A23187. Both Ang II and A23187 caused a rapid increase in the binding of GTP to p21(Ras), which was nearly abolished by genistein and calmidazolium. Transfection with the dominant negative mutant of Ras and the Ras inhibitor manumycin completely inhibited Ang II induced ERK activation. It was also found for the first time that cardiac fibroblasts abundantly expressed Ca2+-sensitive tyrosine kinase Pyk2/CAKbeta/RAFTK and that Ang II markedly induced its activation in a Ca2+/calmodulin-sensitive manner. Overexpression of the dominant negative mutant of Pyk2 significantly attenuated Ang II or A23187-induced ERK activities (36% and 38% inhibition compared with that in mock-transfected cells, respectively) and ERK tyrosine phosphorylation levels, as well as an increase in the binding of GTP to p21(Ras). These findings demonstrate that in cardiac fibroblasts, Ang II induced Ras/ERK activation is dominantly regulated by Gq-coupled Ca2+/calmodulin signaling and that Pyk2 plays an important role in the signal transmission for efficient activation of the Ang II induced Ras/ERK pathway.
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PMID:Role of calcium-sensitive tyrosine kinase Pyk2/CAKbeta/RAFTK in angiotensin II induced Ras/ERK signaling. 977 61

The ras-related protein Rho p21 regulates various actin-dependent functions, including smooth muscle contraction. However, the precise mechanism of action of Rho p21 is still not clear. We report here that Rho A is a key regulator of agonist-induced contractile effects in rabbit colonic smooth muscle. Endothelin-1 and C2 ceramide were used. Both seem to activate phosphoinositide 3-kinase (PI 3-kinase) through G protein and pp60(src), respectively. Immunoprecipitation and immunoblotting revealed one form of 21-kDa Rho A that translocated from the cytosol to the membrane in response to stimulation by either endothelin (10(-7) M) or ceramide (10(-7) M) ( approximately 30% increase at 30 s that was sustained at 4 min). The translocation of Rho A to the membrane was confirmed by immunostaining. The translocation of Rho A was inhibited by Clostridium botulinum C3 exoenzyme, which ADP ribosylated Rho A, but was not inhibited by the pp60(src) inhibitor herbimycin A or by the protein kinase C (PKC) inhibitor calphostin C, suggesting that Rho A may be upstream of pp60(src) and PKC or may belong to a different pathway than these proteins. Both ceramide- and endothelin-induced PI 3-kinase activation was inhibited by C3 exoenzyme pretreatment. However, the C3 exoenzyme inhibited endothelin- but not ceramide-induced mitogen-activated protein kinase phosphorylation, indicating that Rho regulates ceramide- and endothelin-induced contraction through different pathways. Furthermore, the dominant negative form of Rho (N19Rho) inhibited the actin binding protein, 27-kDa heat shock protein (HSP27), reorganization in response to ceramide and endothelin observed under confocal microscopy.
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PMID:Rho A regulates sustained smooth muscle contraction through cytoskeletal reorganization of HSP27. 984 84

During the last 10 years, multiple signal transduction pathways within cells have been discovered. These pathways have been linked to the regulation of many diverse cellular events such as proliferation, senescence, differentiation and apoptosis. This review will focus upon the many roles of signaling by the p42/p44 mitogen-activated protein (MAP) kinase pathway. Recent evidence suggests that signaling by the MAP kinase pathway can both enhance proliferation by increased expression of molecules such as cyclin D1, but also cause growth arrest by increased expression of molecules such as the cyclin kinase inhibitor protein p21(Cip-1/MDA6/WAF1). These differential effects on growth have been correlated to the amplitude and duration of the MAP kinase activity signal. Furthermore several laboratories are reporting data suggesting that inhibition of the MAP kinase pathway, as well as a family of upstream MAP kinase activators, the protein kinase C family, represent an important route to both radio- and chemo-sensitization of tumor cells. Herein, we describe the historical discovery and characterization of the MAP kinase pathway. In addition we describe potential mechanisms by which inhibition of protein kinase C, the MAP kinase pathway, and potentially of p21(Cip-1/MDA6/WAF1) expression, may alter the sensitivities of leukemic and carcinoma cells to cytotoxic insults, leading to increased apoptosis and loss of clonogenicity.
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PMID:The roles of signaling by the p42/p44 mitogen-activated protein (MAP) kinase pathway; a potential route to radio- and chemo-sensitization of tumor cells resulting in the induction of apoptosis and loss of clonogenicity. 984 14

1. The aim of this study was to determine whether different signal transduction mechanisms underlie the Ca2+ sensitizing effects of guanosine 5'-O-(3-thiotriphosphate) (GTP(gamma)S) and receptor agonists on beta-escin-skinned smooth muscle of rabbit mesenteric artery. 2. In the homogenate of the beta-escin-skinned arterial strip, C3 exoenzyme of Clostridium botulinum catalyzed the [32P]-ADP-ribosylation of only one protein that had the same molecular mass as the protein detected in Western blots with anti-rho p21 antibody. Pretreatment of preparations with C3 resulted in great inhibition of GTP(gamma)S-induced Ca2+ sensitization, although the effect of GTP(gamma)S at higher concentrations (> or = 30 microM) was not completely blocked by this treatment. In contrast, the enhancement by phenylephrine and histamine, in the presence of guanosine 5'-triphosphate, of the Ca2+-induced contraction was not affected by C3 pretreatment. 3. The protein kinase C (PKC) inhibitors calphostin C and staurosporine completely eliminated the enhancement by phorbol ester 12,13-dibutyrate of the Ca2+-induced contraction. However, these PKC inhibitors had no effect on GTP(gamma)S- and receptor agonist-induced Ca2+ sensitization. 4. The tyrosine kinase inhibitors genistein and tyrphostin 25 caused an irreversible and complete block of the enhancement by GTP(gamma)S of the Ca2+-induced contraction without affecting this Ca2+ contraction. The inactive genistein analogue daidzein did not modify the effect of GTP(gamma)S. The Ca2+ sensitizing effects of phenylephrine and histamine were also blocked by these tyrosine kinase inhibitors. 5. These results suggest that rho p21 predominantly mediates GTP(gamma)S-induced Ca2+ sensitization of beta-escin-skinned smooth muscle of rabbit mesenteric artery, while the Ca2+ sensitizing actions of heterotrimeric G protein-coupled receptor agonists do not involve this small G protein. However, it seems that tyrosine phosphorylation, but not PKC activation, plays an important role in both of the rho p21 protein- and heterotrimeric G protein-mediated Ca2+ sensitization mechanisms.
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PMID:Tyrosine phosphorylation as a convergent pathway of heterotrimeric G protein- and rho protein-mediated Ca2+ sensitization of smooth muscle of rabbit mesenteric artery. 988 56

p21(WAF1) inhibits cyclin-cyclin-dependent kinase (Cdk) complexes, causing cell cycle arrest. p21(WAF1) contains p53-binding sites in its promoter and expression of p21(WAF1) is induced by functional p53. In the present work, we have studied the role of protein kinase C (PKC) in the induction of p21(WAF1) and show that induction of p21(WAF1) expression can occur by activation of PKC in cells having no p53. Human ovarian carcinoma cells, SKOV-3, lack p53 protein and PMA, a potent activator of PKC, did not induce p53. PMA increased the expression of p21(WAF1) mRNA both in these cells and in other cells which do not contain p53 (THP-1 and U937). Treatment of human embryonic fibroblasts, WI38, with PMA also induced the accumulation of p21(WAF1) without affecting p53 levels. However, PMA did not increase levels of p21(WAF1) mRNA in cells where either the PKC or the mitogen-activated protein kinase pathway was blocked. Furthermore, treatment of cells with various phorbol ester derivatives which activate PKC resulted in the induction of p21(WAF1) in SKOV-3 cells. In contrast, phorbol esters which do not activate PKC failed to induce p21(WAF1) expression. PMA increased the transcriptional rate of p21(WAF1) and activated the transcription of a luciferase reporter gene, controlled by the p21 promoter, in SKOV-3 cells with or without a p53 consensus-binding sequence. By contrast, PMA markedly stabilized p21(WAF1) mRNA; the half-life (t1/2) of p21(WAF1) in PMA-treated cells was >8 h compared with <1 h in untreated cells. These findings provide evidence that the PKC pathway induces expression of p21(WAF1) independently of p53. Our present study also suggests that the accumulation of p21(WAF1) transcripts by PMA occurs mainly at post-transcriptional level.
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PMID:p21WAF1 expression by an activator of protein kinase C is regulated mainly at the post-transcriptional level in cells lacking p53: important role of RNA stabilization. 989 8

Activation of protein kinase C (PKC) inhibits cell cycle progression at the G1/S and G2/M transitions. We found that phorbol 12-myristate 13-acetate (PMA) induced upregulation of p21, not only in MCF-7 cells arrested in the G1 phase as previously shown, but also in cells delayed in the G2 phase. This increase in p21 in cells accumulated in the G1 and G2/M phases of the cell cycle after PMA treatment was inhibited by the PKC inhibitor GF109203X. This indicates that PKC activity is required for PMA-induced p21 upregulation and cell cycle arrest in the G1 and G2/M phases of the cell cycle. To further assess the role of p21 in the PKC-induced G2/M cell cycle arrest independently of its G1 arrest, we used aphidicolin-synchronised MCF-7 cells. Our results show that, in parallel with the inhibition of cdc2 activity, PMA addition enhanced the associations between p21 and either cyclin B or cdc2. Furthermore, we found that after PMA treatment p21 was able to associate with the active Tyr-15 dephosphorylated form of cdc2, but this complex was devoid of kinase activity indicating that p21 may play a role in inhibition of cdc2 induced by PMA. Taken together, these observations provide evidence that p21 is involved in integrating the PKC signaling pathway to the cell cycle machinery at the G2/M cell cycle checkpoint.
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PMID:Involvement of p21 in the PKC-induced regulation of the G2/M cell cycle transition. 1003 43

It has been known for many years that long-chain fatty acids derived from endogenous metabolism and/or nutrition can act as second messengers and regulators of cell signaling pathways. For example, fatty acids regulate the activity of protein kinase C (PKC) in a mechanism distinct from activation by diacylglycerol. Like PKC activators such as phorbol esters, essential fatty acids activate PKC and in doing so modulate the activity of growth factor receptors such as epidermal growth factor receptor (EGFR). Unsaturated fatty acids can inhibit GTPase activating protein, thereby quenching signals from p21-ras. These studies have shown that fatty acids can influence numerous signaling pathways and that these small lipophilic substances may be ancient second messengers. Fatty acids are also known modulators of the carcinogenic process, showing distinct tissue-specific pro- or anticancer effects. However, the reason for such a dichotomous effect on cellular processes has not been adequately described. In this article, the inclusion of a steroid hormone receptor-signaling pathway in mediating fatty acids' effects will be summarized. This signaling molecule has been deemed the peroxisome proliferator-activated receptor (PPAR) and has been extensively examined in regard to its response to xenobiotic, fatty acid-like chemicals (peroxisome proliferators, PP). PP, like fatty acids, activate PPAR and modulate tissue-specific responses. The goal of this review is to describe a potential role for PPAR in mediating the effects of fatty acids on gene expression, cell growth, differentiation and apoptosis.
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PMID:Peroxisome proliferator-activated receptors: a critical link among fatty acids, gene expression and carcinogenesis. 1006 36

Numerous articles and several reviews have been published on the role of antioxidants, and diet and lifestyle modifications in cancer prevention. However, the potential role of these factors in the management of human cancer have been largely ignored. Extensive in vitro studies and limited in vivo studies have revealed that individual antioxidants such as vitamin A (retinoids), vitamin E (primarily alpha-tocopheryl succinate), vitamin C (primarily sodium ascorbate) and carotenoids (primarily polar carotenoids) induce cell differentiation and growth inhibition to various degrees in rodent and human cancer cells by complex mechanisms. The proposed mechanisms for these effects include inhibition of protein kinase C activity, prostaglandin E1-stimulated adenylate cyclase activity, expression of c-myc, H-ras, and a transcription factor (E2F), and induction of transforming growth factor-beta and p21 genes. Furthermore, antioxidant vitamins individually or in combination enhance the growth-inhibitory effects of x-irradiation, chemotherapeutic agents, hyperthermia, and biological response modifiers on tumor cells, primarily in vitro. These vitamins, individually, also reduce the toxicity of several standard tumor therapeutic agents on normal cells. Low fat and high fiber diets can further enhance the efficacy of standard cancer therapeutic agents; the proposed mechanisms for these effects include the production of increased levels of butyric acid and binding of potential mutagens in the gastrointestinal tract by high fiber and reduced levels of growth promoting agents such as prostaglandins, certain fatty acids and estrogen by low fat. We propose, therefore, a working hypothesis that multiple antioxidant vitamin supplements together with diet and lifestyle modifications may improve the efficacy of standard and experimental cancer therapies.
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PMID:High doses of multiple antioxidant vitamins: essential ingredients in improving the efficacy of standard cancer therapy. 1006 54

Recent studies have provided insight into the function of important neisserial adhesins (pili and Opa) and their interaction with cellular receptors, including members of heparan sulfate proteoglycan, CD66, and integrin receptor families. These interactions not only allow colonization of the human mucosa but also stimulate cellular signaling cascades involving phosphatidylcholine-dependent phospholipase C, acidic sphingomyelinase and protein kinase C in epithelial cells, and Src-related kinases, Rac1, p21-activated kinase, and Jun N-terminal kinase in phagocytic cells. Activation of these pathways is essential for cellular entry and intracellular accommodation of the pathogens but also leads to early induction of cytokine release, thus priming the immune response. Detailed knowledge of the cellular signaling cascades that are activated by infection will aid us in applying both current and novel interfering drugs (in addition to classical antibiotic therapy) as therapy and prophylaxis for persistent or otherwise difficult-to-treat bacterial infections, including periodontal infections.
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PMID:Pathogenic neisseriae: complexity of pathogen-host cell interplay. 1019 59


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