EC:2.7.11.13 - FACTA Search

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

Frequent consumption of soy and soy-based products is associated with reduced cancer incidence particularly for breast, colon, and prostate cancer. In this study, we examined the effect of crude soy saponin extract on PMA (phorbol 12-myristate 13-acetate)-induced inflammatory responses. Human adenocarcinoma cells (HT-29) were treated with various concentrations of saponin extract for 72 h. Cell growth was measured at 24, 48 and 72 h of incubation, and the PMA-induced expressions of cyclooxygenase-2 (COX-2), protein kinase C (PKC), and IkappaBalpha were determined. The results indicate that crude saponin extract decreased cell growth in a dose- and time-dependent manner. Crude soy saponin extract suppressed the degradation of IkappaBalpha in PMA-stimulated cells, while COX-2 and PKC expressions were significantly down-regulated. These findings support the hypothesis that the soy saponins reduce the risk of colon tumorigenesis possibly by suppressing inflammatory responses.
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PMID:Antiproliferative crude soy saponin extract modulates the expression of IkappaBalpha, protein kinase C, and cyclooxygenase-2 in human colon cancer cells. 1517 14

A subset of quiescent memory CD4 T cells harboring integrated but transcriptionally silent proviruses poses a currently insurmountable barrier to the eradication of the human immunodeficiency virus (HIV) in infected patients. Induction of HIV gene expression in these latently infected cells by immune activating agents has been proposed as one approach to confer sensitivity to antiretroviral therapy. Interest has recently focused on the non-tumor-promoting phorbol ester, prostratin, as a potential agent to activate latent HIV proviruses. Using multiple Jurkat T cell lines containing integrated but transcriptionally latent HIV proviruses (J-Lat cells), we now demonstrate that prostratin effectively activates HIV gene expression in these latently infected cells. We further show that prostratin acts by stimulating IKK-dependent phosphorylation and degradation of IkappaBalpha, leading to the rapid nuclear translocation of NF-kappaB and activation of the HIV-1 long terminal repeat in a kappaB enhancer-dependent manner. In contrast, NFAT and AP-1 are not induced by prostratin. Using chromatin immunoprecipitation assays to identify host transcription factors recruited to the latent HIV-1 promoter in living cells, we find that prostratin induces RelA binding. Analysis of potential upstream signal transducers demonstrates that prostratin stimulates membrane translocation of classical, novel, and atypical protein kinase C (PKC) isoforms. Studies with isoform-specific PKC inhibitors suggest that the novel PKCs play a particularly prominent role in the prostratin response. These findings provide new insights into the molecular pathway through which prostratin antagonizes HIV latency highlighting a central role for the action of NF-kappaB.
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PMID:Prostratin antagonizes HIV latency by activating NF-kappaB. 1528 45

Cytokines, phorbol esters, radiation and chemotherapeutic drugs up-regulate the expression of MnSOD (manganese superoxide dismutase). Using the VA-13 cell line, we studied the regulation of SOD2 upon treatment with PMA. Pre-treatment with CHX (cycloheximide) followed by PMA led to significantly higher levels of MnSOD mRNA compared with those with either agent alone, suggesting de novo synthesis of an inhibitory protein. PMA treatment modulates redox-sensitive transcription factors, therefore we evaluated the effects of this combination treatment upon AP-1 (activator protein 1) and NF-kappaB (nuclear factor kappaB), two trans-acting factors suggested to play a role in SOD2 regulation. Co-administration of CHX and PMA led to a time-dependent increase in the binding activity of NF-kappaB. Therefore we evaluated IkappaBalpha (inhibitory kappaBalpha) and found that co-administration decreased its steady-state level compared with either agent alone, suggesting that enhanced NF-kappaB activation is due to inhibition of IkappaBalpha synthesis. PMA activates PKC (protein kinase C) enzymes which phosphorylate IkappaBalpha, leading to its degradation, therefore we used GF109203X to inhibit PKC activity. Stable transfection utilizing a PMA-responsive element in the human SOD2 gene, showed a concentration-dependent decrease in luciferase and NF-kappaB-binding activity with GF109203X. Western blot analysis indicated the presence of several PKC isoforms in the VA-13 cell line; however, PMA pre-treatment specifically down-regulated alpha and betaI, suggesting a role for one or more of these proteins in SOD2 induction. Taken together, these results indicate that the PKC pathway leading to SOD2 induction proceeds at least in part through NF-kappaB and that inhibition of IkappaBalpha synthesis might serve as a potential pharmacological approach to up-regulate MnSOD.
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PMID:IkappaBalpha (inhibitory kappaBalpha) identified as labile repressor of MnSOD (manganese superoxide dismutase) expression. 1533 Jul 61

Gastric epithelial cells were incubated with a panel of clinical isolates of Helicobacter pylori, including nonulcer dyspepsia with gastritis (HS, n = 20), gastric ulcer (HU, n = 20), duodenal ulcer (HD, n = 21), and gastric cancer (HC, n = 20). HC strains induced a higher cyclooxygenase-2 (COX-2) expression than those from HS, HD, and HU. The bacterial virulence factors and the host cellular pathways were investigated. Virulence genes of iceA, vacA, babA2, cagA 3' repeat region, and hrgA failed to show any association with the disease status and COX-2 expression. Methylation-specific polymerase chain reaction revealed HC strains not affecting the methylation status of COX-2 promoter. Nuclear factor (NF)-kappaB, NF-interleukin 6, and cAMP response element were found to be involved in COX-2 induction. We explored a novel NF-kappaB activation pathway. The mutants of TLR2 and TLR9, but not TLR4, inhibited H. pylori-induced COX-2 promoter activity, and neutralizing antibodies for TLR2 and TLR9 abolished H. pylori-induced COX-2 expression. Phosphatidylinositol-specific phospholipase C (PI-PLC), protein kinase C (PKC), and Src inhibitors inhibited COX-2 induction. The dominant-negative mutants of NIK and various IkappaB kinase complexes, including IKKbeta (Y188F), IKKbeta (Y199F), and IKKbeta (FF), inhibited the COX-2 promoter activity. Phosphorylation of GST-IKKbeta (132-206) at Tyr188 and Tyr199 by c-Src was found after H. pylori infection. In summary, H. pylori induces COX-2 expression via activations of NF-kappaB, NF-interleukin 6, the cAMP response element. In NF-kappaB activation, H. pylori acts through TLR2/TLR9 to activate both the cascade of PI-PLCgamma/PKCalpha/c-Src/IKKalpha/beta and the cascade of NIK/IKKalpha/beta, resulting in the IkappaBalpha degradation and the expression of COX-2 gene. The COX-2 overexpression may contribute to the carcinogenesis in patients colonized with these strains.
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PMID:Induction of cyclooxygenase-2 overexpression in human gastric epithelial cells by Helicobacter pylori involves TLR2/TLR9 and c-Src-dependent nuclear factor-kappaB activation. 1545 96

Resveratrol, trans-3,5,4'-trihydroxystilbene, was first isolated in 1940 as a constituent of the roots of white hellebore (Veratrum grandiflorum O. Loes), but has since been found in various plants, including grapes, berries and peanuts. Besides cardioprotective effects, resveratrol exhibits anticancer properties, as suggested by its ability to suppress proliferation of a wide variety of tumor cells, including lymphoid and myeloid cancers; multiple myeloma; cancers of the breast, prostate, stomach, colon, pancreas, and thyroid; melanoma; head and neck squamous cell carcinoma; ovarian carcinoma; and cervical carcinoma. The growth-inhibitory effects of resveratrol are mediated through cell-cycle arrest; upregulation of p21Cip1/WAF1, p53 and Bax; down-regulation of survivin, cyclin D1, cyclin E, Bcl-2, Bcl-xL and clAPs; and activation of caspases. Resveratrol has been shown to suppress the activation of several transcription factors, including NF-kappaB, AP-1 and Egr-1; to inhibit protein kinases including IkappaBalpha kinase, JNK, MAPK, Akt, PKC, PKD and casein kinase II; and to down-regulate products of genes such as COX-2, 5-LOX, VEGF, IL-1, IL-6, IL-8, AR and PSA. These activities account for the suppression of angiogenesis by this stilbene. Resveratrol also has been shown to potentiate the apoptotic effects of cytokines (e.g., TRAIL), chemotherapeutic agents and gamma-radiation. Phamacokinetic studies revealed that the target organs of resveratrol are liver and kidney, where it is concentrated after absorption and is mainly converted to a sulfated form and a glucuronide conjugate. In vivo, resveratrol blocks the multistep process of carcinogenesis at various stages: it blocks carcinogen activation by inhibiting aryl hydrocarbon-induced CYP1A1 expression and activity, and suppresses tumor initiation, promotion and progression. Besides chemopreventive effects, resveratrol appears to exhibit therapeutic effects against cancer. Limited data in humans have revealed that resveratrol is pharmacologically quite safe. Currently, structural analogues of resveratrol with improved bioavailability are being pursued as potential therapeutic agents for cancer.
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PMID:Role of resveratrol in prevention and therapy of cancer: preclinical and clinical studies. 1551 85

NF-kappaB is a family of essential transcription factors involved in both embryonic development and inflammatory responses of the immune system. NF-kappaB can be activated by two pathways, i.e. the canonical (NF-kappaB1) pathway, which acts through the catalytic components of the IkappaB kinase complex and leads to IkappaB phosphorylation, degradation, and subsequent NF-kappaB nuclear translocation, or the non-canonical (NF-kappaB2) pathway, which involves NF-kappaB-induced kinase-dependent proteolytic processing of p100/p52 to yield translocation-competent p52-containing NF-kappaB complexes. We examined the relative roles of the NF-kappaB1 and NF-kappaB2 pathways in TCR/CD28 costimulation. We found that TCR/CD28 costimulation activates the canonical but not the non-canonical NF-kappaB pathway and that the serine/threonine kinase protein kinase C (PKC) is essential for TCR/CD28-mediated canonical NF-kappaB activation in T cells. Importantly, TCR/CD28 costimulation induces higher p52 protein levels in T cells, but this effect is secondary to enhanced de novo synthesis of p100, not to enhanced processing of extant p100; PKC deficiency impairs signal-dependent p52 accumulation because of defects in p100 production. Finally, we found that TCR/CD28 costimulation induces IkappaBalpha, IkappaBbeta, and IkappaBepsilon degradation, and PKC is required for IkappaBalpha and IkappaBepsilon but not IkappaBbeta degradation. PKC acts solely within the canonical pathway to activate NF-kappaB, and PKC deficiency impacts upon p100/p52 processing in a manner that is independent of NF-kappaB-induced kinase.
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PMID:Role for protein kinase Ctheta (PKCtheta) in TCR/CD28-mediated signaling through the canonical but not the non-canonical pathway for NF-kappaB activation. 1553 66

In this study, we investigated the signaling pathway involved in cyclooxygenase-2 (COX-2) expression and prostaglandin E2 (PGE2) release by phorbol 12-myristate 13-acetate (PMA), a protein kinase C (PKC) activator, in human pulmonary epithelial cells (A549). PMA-induced COX-2 expression was attenuated by PKC inhibitors (Go 6976 and Ro 31-8220), a Ras inhibitor (manumycin A), a Raf-1 inhibitor (GW 5074), a MEK inhibitor (PD 098059), and an NF-kappaB inhibitor (PDTC), but not by a tyrosine kinase inhibitor (genistein) or a p38 MAPK inhibitor (SB 203580). PMA also caused the activation of Ras, Raf-1, and ERK1/2. PMA-induced activation of Ras and Raf-1 was inhibited by Ro 31-8220 and manumycin A. PMA-mediated activation of ERK1/2 was inhibited by Ro 31-8220, manumycin A, GW 5074, and PD 098059. Stimulation of cells with PMA caused IkappaBalpha phosphorylation, IkappaBalpha degradation, and the formation of a NF-kappaB-specific DNA-protein complex. The PMA-mediated increase in kappaB-luciferase activity was inhibited by Ro 31-8220, manumycin A, GW5074, PD 098059, and PDTC. Taken together, these results indicate that PMA might activate PKC to elicit activation of the Ras/Raf-1/ERK1/2 pathway, which in turn initiates NF-kappaB activation, and finally induces COX-2 expression and PGE2 release in A549 cells.
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PMID:Phorbol 12-myristate 13-acetate upregulates cyclooxygenase-2 expression in human pulmonary epithelial cells via Ras, Raf-1, ERK, and NF-kappaB, but not p38 MAPK, pathways. 1556 61

Cardiac hypertrophy is a major cause of morbidity and mortality worldwide. The hypertrophic process is mediated, in part, by oxidative stress-mediated signaling pathways. We hypothesized that isorhapontigenin (ISO), a new resveratrol analog, inhibits cardiac hypertrophy by blocking oxidative stress and oxidative stress-mediated signaling pathways. We treated cardiomyocytes with angiotensin II (Ang II) with or without ISO and found that ISO inhibited Ang II-induced cardiac hypertrophy. These effects were associated with a decrease in the levels of reactive oxygen species and H2O2 and the content of intracellular malonaldehyde and an increase in the activities of superoxide dismutase and glutathione peroxidase. Ang II induced the phosphorylation of PKC, Erk1/2, JNK, and p38 in cardiomyocytes and such phosphorylation was inhibited by ISO. ISO also blocked the PKC-dependent PI3K-Akt-GSK3beta/p70S6K pathway. These effects lead to direct or indirect inhibition of NF-kappaB and AP-1 activation. Our results revealed that pretreatment with ISO significantly inhibited Ang II-mediated NF-kappaB through affecting the degradation and phosphorylation of IkappaBalpha and the activity of IKKbeta and AP-1 activation by influencing the expression of c-Fos and c-Jun proteins. In addition, we also established the molecular link between activation of PKC and MAPKs and activation of NF-kappaB and AP-1 in cardiomyocytes. We also found that ISO treatment significantly attenuated heart weight/body weight ratio by approximately 25%, decreased posterior wall thickness and left ventricle diastolic and systolic diameters, and increased 10% fractional shortening in an aortic-banded rat model. Furthermore, treatment with ISO significantly decreased cardiac myocyte size and systolic blood pressure. These findings suggest that ISO prevents the development of cardiac hypertrophy through an antioxidant mechanism involving inhibition of different intracellular signaling transduction pathways.
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PMID:Isorhapontigenin, a new resveratrol analog, attenuates cardiac hypertrophy via blocking signaling transduction pathways. 1560 7

Neurotensin (NT) is released in the gastrointestinal tract and participates in the pathophysiology of colonic inflammation. We have shown that NT mediates acute intestinal inflammation in vivo and stimulates nuclear factor-kappaB-dependent interleukin (IL)-8 expression in nontransformed human colonocytes in vitro. However, the exact mechanisms by which NT induces IL-8 expression have not been elucidated. In this study, we first show that NT stimulates IkappaBalpha phosphorylation and degradation and p65 phosphorylation and transcriptional activity. Inhibition of protein kinase C (PKC) activation significantly attenuates NT-induced IL-8 expression. This effect seems to be mediated through inhibition of IkappaBalpha phosphorylation and degradation and by p65 phosphorylation and transcriptional activity. We also show that intracellular calcium mobilization is necessary for NT-induced phosphorylation of IkappaBalpha and p65, suggesting that a conventional PKC is involved. Furthermore, transfection of a dominant-negative form of PKCalpha significantly reduces NT-induced IL-8 promoter activity. These results indicate that the conventional PKCalpha is an important mediator in the proinflammatory signaling pathway elicited by NT at the colonocyte level.
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PMID:Neurotensin stimulates interleukin-8 expression through modulation of I kappa B alpha phosphorylation and p65 transcriptional activity: involvement of protein kinase C alpha. 1575 6

Mast cells (MC) are major effector cells for allergic diseases. Cross-linking of immunoglobulin E (IgE) and its high-affinity receptor, FcepsilonRI, by antigen initiates a cascade of signaling events leading to nuclear factor (NF)-kappaB activation and tumor necrosis factor (TNF) production. Here, we demonstrated that inhibition of inhibitor of kappaB (IkappaB) kinase (IKK) by a peptide IKK inhibitor or by four individual chemical IKK inhibitors including 15-deoxy-prostaglandin J(2), BMS-345541, SC-514, or sulindac significantly blocked IgE + trinitrophenyl (TNP)-induced TNF production by mouse bone marrow-derived MC (BMMC). Moreover, IgE + TNP induced a rapid phosphorylation of IKKalpha but not IKKbeta in BMMC. IgE + TNP-induced phosphorylation of IKKalpha was accompanied with phosphorylation and degradation of IkappaBalpha, subsequent NF-kappaB activation, and TNF production. Inhibition of IKK by sulindac decreased IKKalpha phosphorylation, IkappaBalpha phosphorylation and degradation, NF-kappaB activation, and TNF production by BMMC. It is interesting that IgE + TNP stimulation also induced a prominent synthesis of IKKalpha and IkappaBalpha. Inhibition of NF-kappaB activity by pyrrolidine dithiocarbomate (PDTC) blocked IgE + TNP-induced IkappaBalpha synthesis. NF-kappaB activity and TNF production were also inhibited when PDTC was used even after IgE + TNP stimulation, suggesting a potential role for the newly synthesized IkappaBalpha in MC activation. In addition, IgE + TNP-induced IKKalpha and IkappaBalpha phosphorylation was inhibited by a protein kinase C (PKC) inhibitor Ro 31-8220. Taken together, our results support a role for the IKK-IkappaB-NF-kappaB pathway, which likely involves PKC in IgE-dependent TNF production by MC. Thus, IKK may serve as a new target for the regulation of MC function in allergy.
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PMID:Inhibition of IKK down-regulates antigen + IgE-induced TNF production by mast cells: a role for the IKK-IkappaB-NF-kappaB pathway in IgE-dependent mast cell activation. 1578 89

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