Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interleukin (IL)-18 is a cloned cytokine that was identified originally as a factor having potent interferon (IFN)-gamma-inducing activity on Kupffer cells. First, we analyzed IL-18 gene expression by reverse transcription-polymerase chain reaction (RT-PCR) in rat thyroid FRTL-5 cells and human thyroid tissue samples. The expression of IL-18 mRNA in FRTL-5 cells was enhanced by thryoid-stimulating hormone (TSH) in a dose-dependent manner. 8-Bromo-cyclic adenosine monophosphate (cAMP) also increased in IL-18 mRNA levels. Furthermore, TGCT clones that exhibited an increase in intracellular cAMP accumulation showed an increased IL-18 mRNA signal when compared to controls. Taken together, these data suggested that the effect of TSH on IL-18 gene expression was mediated by activating protein kinase A. Treatment of FRTL-5 cells with the antithyroid drug, methimazole (MMI), suppressed this stimulatory action of TSH on IL-18 gene expression. Next, we examined IL-18 expression in human thyroid tissue derived from patients with autoimmune thyroid diseases (ATD). RT-PCR and immunohistology demonstrated that human thyroid follicular cells expressed IL-18. Especially in thyroid tissue from a patient with Hashimoto's thyroiditis, expression was more diffuse and extensive, generally observed in close relation to a lymphocytic infiltrate. Also, IL-18 protein was distributed in the same follicles that express Fas-L and HLA-DR. This study is the first to demonstrate the detection of IL-18 in the thyroid gland. The frequent expression of IL-18 in thyrocytes suggests that IL-18 itself might be a secreted immunomodulator in ATD.
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PMID:Thyroid-stimulating hormone induces interleukin-18 gene expression in FRTL-5 cells: immunohistochemical detection of interleukin-18 in autoimmune thyroid disease. 1249 70

Interactions between the protein kinase C activator bryostatin 1 and the cyclin-dependent kinase (CDK) inhibitor flavopiridol (FP) have been examined in human myeloid leukemia cells (U937 and HL-60). Previous studies have demonstrated synergistic induction of apoptosis in leukemic cells exposed to the potent differentiation-inducer phorbol 12-myristate 13-acetate (PMA) in conjunction with FP [L. Cartee et al., Cancer Res., 61: 2583-2591, 2001]. Although bryostatin 1 (10 nM) is a very weak inducer of differentiation compared with PMA in these cells, coadministration of a minimally toxic concentration of FP (100 nM) did not promote bryostatin 1-related maturation but instead caused a marked increase in mitochondrial damage (e.g., cytochrome c release; loss of Deltapsi(m)), caspase activation, poly(ADP-ribose) polymerase cleavage, and apoptosis. Bryostatin 1/FP-induced apoptosis was significantly diminished in cells ectopically expressing dominant-negative Fas-associated death domain or by coadministration of tumor necrosis factor (TNF)-alpha soluble receptors, implicating the extrinsic pathway in bryostatin 1/FP actions. Enhanced apoptosis in bryostatin 1/FP-treated cells was accompanied by down-regulation of Mcl-1 and a sustained increase in TNF-alpha release. The selective protein kinase C inhibitor GFX blocked TNF-alpha and cytochrome c release in bryostatin 1/FP-treated cells and attenuated apoptosis. Finally, coadministration of bryostatin 1 (or PMA) with FP induced a marked increase in apoptosis in U937 cells ectopically expressing an NH(2)-terminal phosphorylation loop-deleted Bcl-2 protein, which are otherwise highly resistant to FP-mediated lethality. Taken together, these findings suggest that synergistic induction of apoptosis by bryostatin 1 and FP does not stem from disruption of the leukemic cell maturation process but instead results from enhanced release of TNF-alpha and activation of the extrinsic apoptotic cascade, culminating in cell death.
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PMID:Protein kinase C-dependent activation of the tumor necrosis factor receptor-mediated extrinsic cell death pathway underlies enhanced apoptosis in human myeloid leukemia cells exposed to bryostatin 1 and flavopiridol. 1253 76

Opioid effects on tumor growth have been a controversial topic of discussion. In the present study, morphine inhibited tumor cell proliferation at concentrations of >or=10 micro M. This was primarily caused by inhibition of cell cycle progression from G(1) to S phase. At higher concentrations (>or=500 micro M for 24 h), morphine also caused cell death. In nude mice, morphine significantly reduced the growth of MCF-7 and MDA-MB231 tumors but had no effect on HT-29 tumor growth. In these experiments, morphine plasma concentrations were similar to those found in cancer patients receiving chronic morphine treatment for pain relief (0.9-3.4 micro M). In MCF-7 and MDA-MB231 cells, morphine caused a naloxone (Nx)- and pertussis toxin-sensitive, concentration-dependent increase of GTPase activity, indicating that morphine signals could be transduced by opioid receptors via a G protein. However, the antiproliferative effects of morphine were not antagonized by Nx, pertussis toxin, forskolin, and 8-bromo-cAMP, suggesting that the typical opioid receptor-coupled signaling cascade involving the G(i), adenylyl cyclase, and protein kinase A was not involved. Instead, morphine caused an NH(2)-terminal phosphorylation of p53 at Ser(9) and/or Ser(15) and a stabilization of p53 in MCF-7 cells that express wild-type p53. p53 phosphorylation was not antagonized by Nx and resulted in an increase of p53-dependent proteins including p21, Bax, and the death receptor Fas. Blockade of Fas by Fas-fusion protein or inhibition of caspase 8 resulted in a partial inhibition of morphine-induced apoptosis. In addition, Fas ligand only induced apoptosis when administered together with morphine. However, the sensitivity of the tumor cells toward Fas ligand remained low. HT-29 cells, which express dominant negative p53 and show no increase of GTPase activity when treated with morphine, were less sensitive in vitro and were not affected in vivo. Our results suggest that morphine, alone or in combination with Nx, may reduce the growth of certain tumors, apparently in part through activation of p53.
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PMID:G protein-independent G1 cell cycle block and apoptosis with morphine in adenocarcinoma cells: involvement of p53 phosphorylation. 1270 72

Airway epithelial damage is a feature of persistent asthma. Treatment with inhaled and oral corticosteroids may suppress inflammation and gain clinical control despite continued epithelial damage. We have previously demonstrated that corticosteroids elicit apoptosis of airway epithelial cells in culture. beta-Adrenergic receptor agonists are commonly used in asthma therapy and can inhibit corticosteroid-induced apoptosis of eosinophils. We tested the hypothesis that beta-adrenergic agonists would inhibit corticosteroid-induced airway epithelial cell apoptosis in cultured primary airway epithelial cells and in the cell line 1HAEo-. Albuterol treatment inhibited dexamethasone-induced apoptosis completely but did not inhibit apoptosis induced by Fas receptor activation. The protective effect of albuterol was duplicated by two different analogs of protein kinase A. The protective effect was not associated with increased translocation of the glucocorticoid receptor to the nucleus nor with changes in glucocorticoid receptor-mediated transcriptional activation or repression. We demonstrate that beta-adrenergic agonists can inhibit corticosteroid-induced apoptosis but not apoptosis induced by Fas activation. These data suggest that one potential deleterious effect of corticosteroid therapy in asthma can be prevented by concomitant beta-adrenergic agonist treatment.
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PMID:Beta-adrenergic agonists inhibit corticosteroid-induced apoptosis of airway epithelial cells. 1273 77

IFNs are a family of cytokines with pleiotropic biological effects mediated by scores of responsive genes. IFNs were the first human proteins to be effective in cancer therapy and were among the first recombinant DNA products to be used clinically. Both quality and quantity of life has been improved in response to IFNs in various malignancies. Despite its beneficial effects, unraveling the mechanisms of the anti-tumor effects of IFN has proven to be a complex task. IFNs may mediate anti-tumor effects either indirectly by modulating immunomodulatory and anti-angiogenic responses or by directly affecting proliferation or cellular differentiation of tumor cells. Both direct or indirect effects of IFNs result from induction of a subset of genes, called IFN stimulated genes (ISGs). In addition to the ISGs implicated in anti-viral, anti-angiogenic, immunomodulatory and cell cycle inhibitory effects, oligonucleotide microarray studies have identified ISGs with apoptotic functions. These include TNF-alpha related apoptosis inducing ligand (TRAIL/Apo2L), Fas/FasL, XIAP associated factor-1 (XAF-1), caspase-4, caspase-8, dsRNA activated protein kinase (PKR), 2'5'A oligoadenylate synthetase (OAS), death activating protein kinases (DAP kinase), phospholipid scramblase, galectin 9, IFN regulatory factors (IRFs), promyelocytic leukemia gene (PML) and regulators of IFN induced death (RIDs). In vitro IFN-alpha, IFN-beta and IFN-gamma induced apoptosis in multiple cell lines of varied histologies. This review will emphasize possible mechanisms and the role of ISGs involved in mediating apoptotic function of IFNs.
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PMID:Apoptosis and interferons: role of interferon-stimulated genes as mediators of apoptosis. 1276 84

We previously identified the Fas-associated factor FAF1 as an in vitro substrate of protein kinase CK2 and determined Ser289 and Ser291 as phosphorylation sites. Here we demonstrate that these two serine residues are the only sites phosphorylated by CK2 in vitro, and that at least one site is phosphorylated in vivo. Furthermore, we analyzed putative physiological functions of FAF1 phosphorylation. The ability of FAF1 to potentiate Fas-induced apoptosis is not influenced by the FAF1 phosphorylation status; however, the nuclear import of a phosphorylation-deficient FAF1 mutant was delayed in comparison to wild-type FAF1.
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PMID:Protein kinase CK2 phosphorylates the Fas-associated factor FAF1 in vivo and influences its transport into the nucleus. 1283 43

Cyclin E, the regulatory component of the cyclin E/cyclin-dependent kinase (CDK) complex, is required for proliferation and overexpression of this cyclin is associated with many types of human tumors. To elucidate the mechanism by which cyclin E overexpression promotes tumorigenesis, cyclin E was overexpressed in two breast cancer lines: MCF7 and T47D. Cells overexpressing cyclin E display a marked decrease in the expression of Bcl-2, an antiapoptotic protein, and increased levels of the proapoptotic proteins Bad and Bax. The levels of Bcl-X(L) and Mcl-1 remain unchanged. Since the homeostasis of pro- and antiapoptotic proteins was altered, we asked if cyclin E overexpression modifies responses to cytokines. MCF7 cyclin E overexpressing cells have an enhanced sensitivity to Fas, TRAIL, and TNF-alpha-induced apoptosis. T47D cells overexpressing cyclin E have a significant increase in TNF-alpha and TRAIL-induced apoptosis. In conclusion, our results provide a link between expression of cyclin E, deregulation of Bcl-2, and an altered response to cytokine-mediated apoptosis.
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PMID:Cyclin E overexpression enhances cytokine-mediated apoptosis in MCF7 breast cancer cells. 1284 48

Sodium salicylate is known to induce apoptosis in a variety of cancer cells. However, the molecular mechanism for salicylate-induced apoptosis is yet unclear. Here we show that in HCT116 colon carcinoma cells, 10 mM sodium salicylate induces caspase-3 activation and degradation of its substrates, poly(ADP-ribose) polymerase (PARP), beta-catenin, and retinoblastoma (Rb). In contrast, sodium salicylate did not exert any significant effects on the expression of Fas L that is implicated in extrinsic apoptotic pathway and the levels of Bcl-2 family proteins, Bcl-2, Bcl-xsl, and Bad, which are involved in intrinsic apoptotic pathway, and anti-apoptotic molecules, c-IAP1 and HSP73. In addition, 10 mM salicylate induced p53 tumor suppressor protein that plays an important role in cell cycle arrest or apoptosis and the induction seemed to be linked to its phosphorylation at Set 15. To investigate the signal pathways for salicylate-induced apoptosis, we examined the effects of sodium salicylate on protein kinase activities. Sodium salicylate activated p38MAPK through phosphorylation at Thr 180/Tyr 182 and Akt/PKB at Ser 473, whereas it partially activated ERK1/2 through its phosphorylation at Thr 202/Tyr 204. We also show that SB203580 (a specific p38MAPK inhibitor), but not other protein kinase inhibitors (PD98059, LY294002, and wortmannin), significantly prevented salicylate-induced apoptosis. These results suggest that sodium salicylate-induced apoptosis in HCT116 colorectal cancer cells is mediated by p38MAPK.
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PMID:Sodium salicylate induces apoptosis in HCT116 colorectal cancer cells through activation of p38MAPK. 1285 2

Protein phosphatase-directed toxins such as okadaic acid (OA) are general apoptosis inducers. We show that a protein (inhibitor of radiation- and OA-induced apoptosis, Irod/Ian5), belonging to the family of immune-associated nucleotide binding proteins, protected Jurkat T-cells against OA- and gamma-radiation-induced apoptosis. Unlike previously described antiapoptotic proteins Irod/Ian5 did not protect against anti-Fas, tumor necrosis factor-alpha, staurosporine, UV-light, or a number of chemotherapeutic drugs. Irod antagonized a calmodulin-dependent protein kinase II-dependent step upstream of activation of caspase 3. Irod has predicted GTP-binding, coiled-coil, and membrane binding domains. Irod localized to the centrosomal/Golgi/endoplasmic reticulum compartment. Deletion of either the C-terminal membrane binding domain or the N-terminal GTP-binding domain did not affect the antiapoptotic function of Irod, nor the centrosomal localization. The middle part of Irod, containing the coiled-coil domain, was therefore responsible for centrosomal anchoring and resistance toward death. Being widely expressed and able to protect also nonimmune cells, the function of Irod may not be limited to the immune system. The function and localization of Irod indicate that the centrosome and calmodulin-dependent protein kinase II may have important roles in apoptosis signaling.
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PMID:Irod/Ian5: an inhibitor of gamma-radiation- and okadaic acid-induced apoptosis. 1292 64

The mechanism of induction of apoptosis by double-stranded RNA (dsRNA) is not fully characterized. The dsRNA is normally present in extremely low quantities in cells, but following infection with RNA viruses, large quantities of the dsRNA viral replicative intermediate may be produced triggering the antiviral response as well as cell death. In this report, transfection of polyinosinic-polycytidylic acid [poly(I:C)] into NIT 1 cells has been used as a model of intracellular dsRNA-induced beta-cell apoptosis. At 18 h post transfection, 45% of the cells were apoptotic as indicated by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling (TUNEL) staining, and this was accompanied by an increase in nuclear factor kappaB (NF-kappaB) p50/p65 nuclear translocation and cleavage of caspases 3 and 8. The NF-kappaB inhibitor peptide, SN50, significantly reduced caspase-3 activity and the percentage of TUNEL-positive cells, substantiating a role for NF-kappaB in inducing intracellular dsRNA-mediated apoptosis. Concomitantly, RNA-dependent protein kinase activity was observed at 3 h post transfection along with phosphorylation and degradation of inhibitory kappaB-alpha. Expression of TRAIL (TNF-related apoptosis-inducing ligand), Fas, IL-15, and caspase-12 mRNAs was up-regulated in the presence of poly(I:C) but not when SN50 was also added. In contrast, there was no change detected in Fas, Fas-associated death domain, Bcl-2, Bcl-xl, Bax, p53, or XIAP(X-linked inhibitor of apoptosis protein) expression up to 12 h after poly(I:C) transfection. In addition, caspase-12 was cleaved, and phosphorylation of eukaryotic initiation factor 2alpha occurred, suggesting that an endoplasmic reticulum stress pathway was involved in addition to NF-kappaB induction of an extrinsic pathway, possibly mediated by TNF-related apoptosis-inducing ligand.
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PMID:Nuclear factor-kappaB translocation mediates double-stranded ribonucleic acid-induced NIT-1 beta-cell apoptosis and up-regulates caspase-12 and tumor necrosis factor receptor-associated ligand (TRAIL). 1296 48


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