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)

Many cytokines have dual functions of promoting or inhibiting cell proliferation; however, the molecular mechanism of the dual functions of cytokines is not well understood. Under normal conditions, interleukin (IL)-3 is required for Ba/F3 cell proliferation, whereas interferon (IFN)-gamma inhibits Ba/F3 cell proliferation. It is known that Stat1 play a major role in inhibition of cell growth in response to IFN-gamma. We have examined the possibility of whether IFN-gamma can act as a growth-promoting cytokine if the Stat1 function is selectively blocked. We have established variant Ba/F3 cell lines in which Stat1 function is inhibited by a dominant-negative Stat1 mutant. Intriguingly, once Stat1 function is inhibited, IFN-gamma can replace IL-3 acting as an essential growth factor for cell proliferation. To understand the molecular mechanism of regulation of cell proliferation by the cytokines, the signaling pathways and gene induction by IL-3 and IFN-gamma are further studied. Although IL-3 activates mitogenic-activated protein kinase and Akt kinase, IFN-gamma does not. Interestingly, both IL-3 and IFN-gamma induce expression of the c-Myc gene that is not dependent on the Stat1 activity. Expression of a dominant-negative mutant Myc can block IFN-gamma-mediated Ba/F3 cell proliferation, suggesting that c-Myc gene induction is required for IFN-gamma-mediated cell proliferation. These findings suggest that IFN-gamma intrinsically and simultaneously induces specific and conflicting signaling pathways and transcriptional programs that contribute to the potential dual effects of IFN-gamma in promoting or inhibiting cell proliferation.
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PMID:Interferon-gamma has dual potentials in inhibiting or promoting cell proliferation. 1062 20

To clarify the biological significance of double-stranded RNA-dependent protein kinase (PKR), an interferon (INF)-inducible substance, we investigated (1) PKR gene expression and the (2) effect of IFN-gamma on PKR gene expression in human endometrium. By Northern blot analysis, PKR mRNA was detected as a 2.5 kb band in human endometrium throughout the menstrual cycle and decidua in early pregnancy. The addition of IFN-gamma to culture medium increased the PKR mRNA level in a dose-dependent manner in cultured endometrial stromal cells. These results suggest that IFN-gamma, which is reported to have an inhibitory effect on cell proliferation, plays an important role in human endometrial function by mediating PKR gene expression.
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PMID:Gene expression of double-stranded RNA-dependent protein kinase in the human endometrium and decidua. 1063 Apr 6

Interferons (IFNs) inhibit cell growth in a Stat1-dependent fashion that involves regulation of c-myc expression. IFN-gamma suppresses c-myc in wild-type mouse embryo fibroblasts, but not in Stat1-null cells, where IFNs induce c-myc mRNA rapidly and transiently, thus revealing a novel signaling pathway. Both tyrosine and serine phosphorylation of Stat1 are required for suppression. Induced expression of c-myc is likely to contribute to the proliferation of Stat1-null cells in response to IFNs. IFNs also suppress platelet-derived growth factor (PDGF)-induced c-myc expression in wild-type but not in Stat1-null cells. A gamma-activated sequence element in the promoter is necessary but not sufficient to suppress c-myc expression in wild-type cells. In PKR-null cells, the phosphorylation of Stat1 on Ser727 and transactivation are both defective, and c-myc mRNA is induced, not suppressed, in response to IFN-gamma. A role for Raf-1 in the Stat1-independent pathway is revealed by studies with geldanamycin, an HSP90-specific inhibitor, and by expression of a mutant of p50(cdc37) that is unable to recruit HSP90 to the Raf-1 complex. Both agents abrogated the IFN-gamma-dependent induction of c-myc expression in Stat1-null cells.
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PMID:Regulation of c-myc expression by IFN-gamma through Stat1-dependent and -independent pathways. 1063 30

Death-associated protein kinase (DAP-kinase) is a Ca(+2)/calmodulin-regulated serine/threonine kinase with a multidomain structure that participates in apoptosis induced by a variety of signals. To identify regions in this protein that are critical for its proapoptotic activity, we performed a genetic screen on the basis of functional selection of short DAP-kinase-derived fragments that could protect cells from apoptosis by acting in a dominant-negative manner. We expressed a library of randomly fragmented DAP-kinase cDNA in HeLa cells and treated these cells with IFN-gamma to induce apoptosis. Functional cDNA fragments were recovered from cells that survived the selection, and those in the sense orientation were examined further in a secondary screen for their ability to protect cells from DAP-kinase-dependent tumor necrosis factor-alpha-induced apoptosis. We isolated four biologically active peptides that mapped to the ankyrin repeats, the "linker" region, the death domain, and the C-terminal tail of DAP-kinase. Molecular modeling of the complete death domain provided a structural basis for the function of the death-domain-derived fragment by suggesting that the protective fragment constitutes a distinct substructure. The last fragment, spanning the C-terminal serine-rich tail, defined a new regulatory region. Ectopic expression of the tail peptide (17 amino acids) inhibited the function of DAP-kinase, whereas removal of this region from the complete protein caused enhancement of the killing activity, indicating that the C-terminal tail normally plays a negative regulatory role. Altogether, this unbiased screen highlighted functionally important regions in the protein and revealed an additional level of regulation of DAP-kinase apoptotic function that does not affect the catalytic activity.
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PMID:A functional genetic screen identifies regions at the C-terminal tail and death-domain of death-associated protein kinase that are critical for its proapoptotic activity. 1067 1

The RNA-dependent protein kinase (PKR) is implicated in the antiviral and antiproliferative actions of interferon (IFN). As an extension of our structural characterization of the exon-intron organization of the mouse Pkr gene, we now have isolated and characterized the mouse Pkr promoter region required for IFN-inducible transcription. Transient transfection analyses, using reporter constructs possessing various 5'-flanking fragments of the Pkr gene, led to the identification of a functional IFN-inducible promoter. A single IFN-stimulated response element (ISRE) was present in a minimal 44-nt TATA-less promoter identified by deletion analysis; the 13-nt ISRE differed from previously described ISRE elements in that the 3'-nt was a purine instead of a pyrimidine. The sequence immediately upstream of the ISRE possessed the 15-nt KCS element that was exactly conserved in sequence and position between the mouse and human Pkr promoters. A single gamma IFN-activated sequence (GAS)-like element and multiple recognition sites for factors including NF-kappaB and NF-IL6 involved in responses to various cytokine and hormone signals in inflammatory responses were also present in the 5'-flanking region. Northern blot analysis showed efficient IFN-alpha induced accumulation of 2.4kb, 4.5kb and approx. 6kb Pkr transcripts, but neither IFN-gamma nor IL-6 induced detectable Pkr mRNA accumulation in L cells.
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PMID:Mouse interferon-inducible RNA-dependent protein kinase Pkr gene: cloning and sequence of the 5'-flanking region and functional identification of the minimal inducible promoter. 1076 60

In attempts to elucidate the pathogenic mechanisms involved in neurodegeneration in AIDS patients with cognitive deficits, the possible effect of HIV-1 transmembrane envelope protein gp41 on expression of the membrane inhibitor of complement mediated cytolysis (CD59) was assessed in human neuronal (SK-N-SH) and astroglial (T98G) cell lines. Western blotting analyses demonstrated that an immunodominant (ID, aa 598-613) gp41 peptide as well as the recombinant gp41 protein encompassing this domain markedly reduced CD59 level in a dose dependent manner whereas p24 and control peptide had little effect. RT-PCR showed that ID peptide also elicited a reduction in the expressed CD59 mRNA level. This gp41 peptide apparently down-regulated phorbol 12,13-dibutyrate induced elevation of CD59 at the protein and mRNA levels in a manner similar to that conferred by protein kinase C inhibitor, H-7 or staurosporine in SK-N-SH. Interestingly, proinflammatory cytokines such as IL-1beta or IFN-gamma as well as LPS greatly decreased CD59 in SK-N-SH and to a lesser extent in T98G whereas TNF-alpha did not significantly alter it. In contrast, antioxidants and anti-inflammatory agents enhanced CD59 expression reversing gp41 peptide mediated inhibitory effect in SK-N-SH. Our data suggest that high level of gp41 or its metabolites as well as impaired protein kinase response, chronic inflammation or antioxidant depletion within HIV-1 infected brains may be associated with a diminished expression of CD59 which would render neuronal cells to susceptible to indirect bystander lysis in the presence of autologous complement.
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PMID:Expression of complement inhibitor protein CD59 in human neuronal and glial cell lines treated with HIV-1 gp41 peptides. 1078 97

The paper presents a review of data on the localization of interferons (IFNs) and IFN system genes and their relationship with human diseases, mainly cancer. Genes of interferon system proteins are located at the sites of breakpoints of the structural chromosome aberrations in cancer. Thus, any of them are rearranged or translocated in various tumor types. As the activity of these genes plays a role in cancer development, their rearrangements may be one of the crucial points in the pathogenesis of some cancer types. Besides, they also take part in organism immunity against viral infections. Transfection experiments with IFN system genes have proved the influence of these genes on cancer behavior and may serve as a basis for clinical gene therapy. IFN-alpha and IFN-beta genes are located at 9p21-22, the site of frequent homozygotic deletions in cancer. Their loss sensitizes cells to the growth inhibitory actions of exogenous IFNs. The IFN-gamma gene, a representative of class II genes, is located at 12q24.1. Transfection of class II IFNs genes to cancer cell lines causes cell proliferation arrest and augments the expression of HLA antigens, which may be clinically useful in stimulating the immune destruction of tumor cells. The interferon regulatory factor 1 (IRF-1) gene is located at 5q31, the site of common deletions in myelodysplastic syndromes (MDS) and secondary leukemias. The loss of heterozygosity of this gene was found in MDS, which proves that IRF-1 may be a tumor suppressor. A transfection of its gene causes neoplastic transformation arrest. The double-stranded RNA-activated protein kinase (PKR) gene is located at 2p21-22, a region which is frequently rearranged in leukemia. Transfection of a wild type PKR gene reverses neoplastic transformation caused by transfection of a mutated PKR gene, proving that PKR acts as a dominant negative cancer suppressor.
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PMID:The genes of interferons and interferon-related factors: localization and relationships with chromosome aberrations in cancer. 1080 49

IL-2 stimulates extracellular signal-regulated protein kinase (ERK) and p38 mitogen-activated protein kinase (MAPK) in various immune cell populations. The functional roles that these kinases play are still unclear. In this study, we examined whether MAPK kinase (MKK)/ERK and p38 MAPK pathways are necessary for IL-2 to activate NK cells. Using freshly isolated human NK cells, we established that an intact MKK/ERK pathway is necessary for IL-2 to activate NK cells to express at least four known biological responses: LAK generation, IFN-gamma secretion, and CD25 and CD69 expression. IL-2 induced ERK activation within 5 min. Treatment of NK cells with a specific inhibitor of MKK1/2, PD98059, during the IL-2 stimulation blocked in a dose-dependent manner each of four sequelae, with inhibition of lymphokine-activated killing induction being least sensitive to MKK/ERK pathway blockade. Activation of p38 MAPK by IL-2 was not detected in NK cells. In contrast to what was observed by others in T lymphocytes, SB203850, a specific inhibitor of p38 MAPK, did not inhibit IL-2-activated NK functions. This data indicate that p38 MAPK activation was not required for IL-2 to activate NK cells for the four functions examined. These results reveal selective signaling differences between NK cells and T lymphocytes; in NK cells, the MKK/ERK pathway and not p38 MAPK plays a critical positive regulatory role during activation by IL-2.
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PMID:IL-2 activation of NK cells: involvement of MKK1/2/ERK but not p38 kinase pathway. 1084 77

The objectives of this study were to determine whether rat aortic smooth muscle cells (RASMC) express arginase and to elucidate the possible mechanisms involved in the regulation of arginase expression. The results show that RASMC contain basal arginase I (AI) activity, which is significantly enhanced by stimulating the cells with either interleukin (IL)-4 or IL-13, but arginase II (AII) expression was not detected under any condition studied here. We further investigated the signal transduction pathways responsible for AI induction. AI mRNA and protein levels were enhanced by addition of forskolin (1 microM) and inhibited by H-89 (30 microM), suggesting positive regulation of AI by a protein kinase A pathway. Genistein (10 microgramg/ml) and sodium orthovanadate (Na(3)VO(4); 10 microM) were used to investigate the role of tyrosine phosphorylation in the control of AI expression. Genistein inhibited, whereas Na(3)VO(4) enhanced the induction of AI by IL-4 or IL-13. Along with immunoprecipitation and immunoblot analyses, these data implicate the JAK/STAT6 pathway in AI regulation. Dexamethasone (Dex) and interferon (IFN)-gamma were investigated for their effects on AI induction. Dex (1 microM) and IFN-gamma (100 U/ml) alone had no effect on basal AI expression in RASMC, but both reduced AI induction by IL-4 and IL-13. In combination, Dex and IFN-gamma abolished AI induction by IL-4 and IL-13. Finally, both IL-4 and IL-13 significantly increased RASMC DNA synthesis as monitored by [(3)H]thymidine incorporation, demonstrating that upregulation of AI is correlated with an increase in cell proliferation. Blockade of AI induction by IFN-gamma, H-89, or genistein also blocked the increase in cell proliferation. These observations are consistent with the possibility that upregulation of AI might play an important role in the pathophysiology of vascular disorders characterized by excessive smooth muscle growth.
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PMID:IL-4 and IL-13 upregulate arginase I expression by cAMP and JAK/STAT6 pathways in vascular smooth muscle cells. 1089 36

In this study, the role of the double-stranded (ds) RNA-dependent protein kinase (PKR) in macrophage activation was examined. dsRNA [polyinosinic:polycytidylic acid (poly IC)]-stimulated inducible nitric oxide synthase, interleukin (IL)-1alpha and IL-1beta mRNA expression, nitrite formation and IL-1 release are attenuated in RAW264.7 cells stably expressing dominant negative (dn) mutants of PKR. The transcriptional regulator nuclear factor (NF)-kappaB is activated by dsRNA, and appears to be required for dsRNA-induced macrophage activation. While dnPKR mutants prevent macrophage activation, they fail to attenuate dsRNA-induced IkappaB degradation or NF-kappaB nuclear localization. The inhibitory actions of dnPKR on dsRNA-induced macrophage activation can be overcome by treatment with interferon (IFN)-gamma, an event associated with PKR degradation. Furthermore, dsRNA + IFN-gamma stimulate inducible nitric oxide synthase expression, IkappaB degradation and NF-kappaB nuclear localization to similar levels in macrophages isolated from PKR(-/-) and PKR(+/+) mice. These findings indicate that both NF-kappaB and PKR are required for dsRNA-induced macrophage activation; however, dsRNA-induced NF-kappaB activation occurs by PKR-independent mechanisms in macrophages. In addition, the PKR dependence of dsRNA-induced macrophage activation can be overcome by IFN-gamma.
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PMID:Potential role of PKR in double-stranded RNA-induced macrophage activation. 1089 17


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