Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Infection of mouse L cells with mengovirus resulted in the activation of a protein kinase (PK) that selectively phosphorylated the small, 38,000-molecular-weight alpha subunit of eucaryotic initiation factor 2 (eIF-2) in vitro. The mengovirus-activated kinase was detected in vitro approximately 3 h after virus adsorption. The ratio of phosphorylated to unphosphorylated eIF-2 also increased in vivo between 3 and 7 h after adsorption. The virus-activated kinase fractionated with the ribosomal pellet and had a high affinity for DEAE-cellulose and Mono Q ion-exchange columns. Gel electrophoresis of the kinase activity eluting from the Mono Q column and silver staining of the gel revealed only one protein band with a molecular mass of 70 kilodaltons. The optimal assay conditions for the mengovirus-activated kinase paralleled those of the double-stranded RNA-activated PK (dsRNA-PK). Lysates from infected cells contained elements capable of activating partially purified dsRNA-PK. These elements were identified as double-stranded RNA by their sensitivity to double-stranded RNase. The phosphorylation of the alpha subunit of eIF-2 coincided with the synthesis of dsRNA in infected cells, suggesting that the mengovirus-activated kinase is the dsRNA-PK. The phosphorylation of the alpha subunit of eIF-2 correlated with the global inhibition of protein synthesis that occurs at late times after infection.
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PMID:The alpha subunit of eucaryotic initiation factor 2 is phosphorylated in mengovirus-infected mouse L cells. 216 23

Infection of astrocytes with Newcastle disease virus stimulated the production of 1,2-diacylglycerol, and resulted in the kinase-dependent expression of mRNAs encoding tumor necrosis factor (TNF), interferon alpha and beta, and interleukin 6. The half-life of TNF mRNA was significantly decreased in the presence of protein kinase inhibitors H-7 and staurosporine, but not in the presence of HA1004. In contrast to the decay of TNF mRNA, the half-lives of other cytokine mRNAs were only minimally affected by the kinase inhibitors. These data indicated that the stability of TNF mRNA was regulated through a novel, kinase-dependent pathway.
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PMID:Protein kinase regulates tumor necrosis factor mRNA stability in virus-stimulated astrocytes. 238 40

We have analysed the expression of vesicular stomatitis virus (VSV) proteins in virus-infected freshly explanted mouse peritoneal macrophages (resistant to virus replication), macrophages aged in vitro (permissive for virus replication) and freshly explanted macrophages from mice treated with antibody to interferon (IFN) alpha/beta (permissive for VSV replication). Our data showed that some VSV proteins (i.e. N/NS and G) were synthesized in virus-infected (1 p.f.u/cell) freshly harvested macrophages at early times after infection (3 to 6 h); the expression of such viral proteins was subsequently inhibited at 18 h post-infection. In contrast, a progressive increase in the expression of VSV proteins was observed in the macrophages aged in vitro and infected with VSV at 1 p.f.u./cell. Infection with a higher m.o.i. (16 p.f.u./cell) resulted in similar viral protein electrophoresis patterns for both aged macrophages and freshly explanted macrophages. Even at low m.o.i. a marked and progressive expression of all VSV proteins was observed in freshly harvested macrophages from mice treated with antibody to mouse IFN-alpha/beta. Higher levels of oligo-2',5'-adenylate synthetase (2-5AS) were found in freshly harvested macrophages than in either aged macrophages or those from mice treated with antibody to IFN. No dsRNA-dependent 67K protein kinase was detected in freshly harvested macrophages or peritoneal cells from untreated mice or mice treated with poly(rI).poly(rC) or Newcastle disease virus. The following conclusions can be drawn from these results. Low levels of spontaneous IFN-alpha/beta are responsible for the time-dependent inhibition of VSV protein synthesis in virus-infected freshly harvested macrophages; high levels of 2-5AS (in the absence of detectable levels of 67K protein kinase) appear to correlate with the progressive inhibition of VSV proteins; this natural antiviral state is highly effective only at low m.o.i.
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PMID:Studies on the mechanism of the interferon-mediated antiviral state to vesicular stomatitis virus in resting mouse peritoneal macrophages. 254 69

Infection of normocholesterolemic, specific-pathogen-free chickens with Marek's disease herpesvirus (MDV) has been shown histologically to lead to chronic atherosclerosis like that in humans. The development of herpesvirus-induced atherosclerosis in vivo and the presence of specific Marek's antigen within aortic cells suggested that MDV infection may modify lipid metabolism and lead to significant lipid accumulation. Experiments reported herein were designed to determine the types and quantity of lipid present in aortas from MDV-infected and uninfected chickens between 2 and 8 months of age following infection and assess one possible mechanism of lipid accumulation by evaluating the effect of MDV infection on aortic cholesterol and cholesteryl ester (CE) metabolism. Chromatographic-fluorometric analyses indicated that at 4 and 8 months of age after MDV inoculation, MDV-infected animals had a significant (P less than 0.05) two-fold to threefold increase in total aortic lipid accumulation characterized by significant increases in cholesterol, CE, triacylglycerol, and phospholipid as compared with aortas from uninfected animals. At 8 months of age, similar increases in aortic lipid accumulation were observed in MDV-infected animals as compared with those animals vaccinated with turkey herpesvirus and later challenged with MDV. CE synthetic activity was increased significantly by 50% at 4 months of age in the MDV-infected group as compared with the uninfected group, which could explain the initial increase in CE accumulation. By 8 months of age, the authors also observed a twofold increase in CE synthetic activity and a 30% and 80% reduction in lysosomal and cytoplasmic CE hydrolytic activities, respectively, in aortas of MDV-infected chickens as compared to controls. Moreover, infection with MDV blocked the activation of cytoplasmic CE hydrolytic activity by dibutyryl cyclic AMP or exogenous cyclic AMP-dependent protein kinase. Taken together, these results suggest that lipid accretion in aortas of MDV-infected chickens results, in part, from alterations in cholesterol/CE metabolism during early stages of the disease. These findings support the hypothesis that human atherosclerosis may result from specific herpesvirus infection which can alter lipid metabolism and lead to lipid accretion.
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PMID:Virus-induced atherosclerosis. Herpesvirus infection alters aortic cholesterol metabolism and accumulation. 293 87

p56lck, a cellular tyrosine protein kinase (EC 2.7.1.112) of the src family, is expressed in essentially all T cells and in some B cells. Expression in nonlymphoid cells is observed only rarely. We have found that mutation of a carboxyl-terminal phosphorylation site, tyrosine-505, reveals an oncogenic activity of this protein. Infection of fibroblasts with a retrovirus encoding wild-type p56lck is without consequence. In contrast, infection with a virus encoding the mutant protein leads to greatly increased phosphorylation of cellular proteins on tyrosine, morphological transformation, and anchorage-independent growth. This suggests that the tyrosine protein kinase activity and the oncogenic potential of p56lck are normally suppressed in vivo by phosphorylation of tyrosine-505. Since similar results were obtained previously with an analogous mutant of c-src, our results suggest that the protein kinase activity of all members of the src family of cytoplasmic tyrosine protein kinases will prove to be regulated by tyrosine phosphorylation at a conserved residue near the carboxyl terminus. Because p56lck is normally expressed only in lymphoid cells, it was possible that p56lck would be without effect in other tissues. The transformation of fibroblasts by mutant p56lck shows that this lymphoid protein can interact productively with nonlymphoid polypeptide substrates.
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PMID:Mutation of a site of tyrosine phosphorylation in the lymphocyte-specific tyrosine protein kinase, p56lck, reveals its oncogenic potential in fibroblasts. 338 Jul 89

A murine retrovirus (MRSV) containing the src gene of Rous sarcoma virus has been shown to cause an erythroproliferative disease in mice (S. M. Anderson and E. M. Scolnick, J. Virol. 46:594-605, 1983). We now demonstrate that this same virus can transform erythroid progenitor cells in vitro. Infection of fetal liver cells or spleen and bone marrow cells from phenylhydrazine-treated adult mice gave rise to colonies of erythroid cells which grew in methylcellulose under conditions not favorable for the growth of normal erythroid cells. The presence of pp60src in the transformed erythroid cells was demonstrated by an immune complex protein kinase assay. The time course of appearance and subsequent differentiation of erythroid colonies indicated that the target cell for MRSV was a 6- to 8-day burst-forming unit. Differentiation of the erythroid progenitors was not blocked by the presence of pp60src, and the cells retained sensitivity to the hormone erythropoietin. In fact, the transformed cells exhibited increased hormone sensitivity since the number, the size, and the extent of hemoglobinization of the colonies were all increased by the addition of small amounts of erythropoietin. MRSV was not susceptible to restriction by the Fv-2 locus, as MRSV could transform hematopoietic cells from C57BL/6 mice. These results indicate that (i) the erythroid proliferation observed in vivo is caused by a direct effect of MRSV on erythroid progenitors and (ii) the transformed erythroid precursors acquire a growth advantage over uninfected cells without losing the ability to differentiate and respond to physiologic regulators.
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PMID:A murine recombinant retrovirus containing the src oncogene transforms erythroid precursor cells in vitro. 393 14

Infection of avian macrophages with Rous sarcoma virus does not induce any changes in the morphology, growth behavior, or expression of macrophage-specific proteins. The absence of cellular transformation does not result from a block in the synthesis of viral proteins, since infectious viruses are released from a majority of cells in the culture. In this report, we examine the synthesis, processing, and functional activity of pp60src in Rous sarcoma virus-infected macrophages to determine whether the absence of transformation is due to an alteration in the functional expression of pp60src. Although the absolute level of pp60src was reduced compared with fibroblasts, the protein exhibited the same phosphorylation pattern and subcellular distribution and was able to phosphorylate immunoglobulin in the immune complex-protein kinase assay. These results imply that the failure of Rous sarcoma virus to transform macrophage may be due to a restriction in the cellular response to a functional src protein, perhaps due to the absence of cellular products which are essential for mediating pp60src-induced transformation.
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PMID:Expression of the Rous sarcoma virus src gene in avian macrophages fails to elicit transformed cell phenotype. 609 71

Infection of NIH/3T3 and Balb/c/3T3 fibroblastic cell lines by Abelson virus results in stable transformation in most cases. We have observed that certain rodent cell lines, including some Balb/c/3T3 sublines, do not maintain stable transformation following infection. Within three to four weeks of infection of these cell lines a large fraction of the cells is not recoverable upon serial passage and appear to be killed. The residual population of cells displays a flat, nontransformed phenotype. Concomitant with this reversion is the loss of the integrated provirus and loss of expression of the Abelson virus transforming protein. This loss of the integrated provirus is specific to transformation-competent viral strains. The effect of Abelson virus on these cells appears to be, in part, due to a lethal effect of the transforming protein on the cells. We have selectively isolated mutants of Abelson virus that stably transform these rodent cell lines without expressing a lethal effect. Analysis of the nucleic acid and protein structure of these mutant virus strains showed that the transforming proteins are shorter, having lost expression of the carboxy-terminal one third of the protein. We suspect that the carboxy-terminal portion of the wild-type Abelson protein may modulate the in vivo expression of the protein kinase activity and that this may cause the transforming protein to have a deleterious effect on certain cell lines.
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PMID:Lethal effect of the Abelson murine leukemia virus transforming gene product. 610 Dec 2

Salmonella typhimurium invades nonphagocytic epithelial and fibroblast cells via a process resembling phagocytosis. We have compared some phenotypes that are involved in S. typhimurium invasion by using different host cell lines, including HeLa, Henle-407, and A431. Infection with either wild-type S. typhimurium, bacterial culture supernatant, or the noninvasive invA mutant was associated with induction of tyrosine phosphorylation of host cell mitogenic activating protein kinase. However, we did not detect induction of tyrosine phosphorylation of the epidermal growth factor receptor in S. typhimurium-infected cells. Treatment with the tyrosine protein kinase inhibitor genistein did not reduce S. typhimurium invasion into any of these cell lines. These results suggest that S. typhimurium invasion is independent of host cell epidermal growth factor receptor activation.
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PMID:Salmonella typhimurium invasion of epithelial cells: role of induced host cell tyrosine protein phosphorylation. 752 3

The vaccinia virus (VV) E3L gene, which encodes a potent inhibitor of the interferon (IFN)-induced, double-stranded RNA (dsRNA)-dependent protein kinase, PKR, is thought to be involved in the IFN-resistant phenotype of VV. The E3L gene products, p25 and p20, act as inhibitors of PKR, presumably by binding and sequestering activator dsRNA from the kinase. In this study we demonstrate that VV with the E3L gene specifically deleted (vP1080) was sensitive to the antiviral effects of IFN and debilitated in its ability to rescue vesicular stomatitis virus from the antiviral effects of IFN. Infection of L929 cells with E3L-minus virus led to rRNA degradation typical of activation of the 2'-5'-oligoadenylate synthetase/RNase L system, and extracts of infected cells lacked the PKR-inhibitory activity characteristic of wild-type VV. The reovirus S4 gene, which encodes a dsRNA-binding protein (sigma 3) that can also inhibit PKR activation by binding and sequestering activator dsRNA, was inserted into vP1080. The resultant virus (vP1112) was partially resistant to the antiviral effects of IFN in comparison with vP1080. Further studies demonstrated that transient expression of the reovirus sigma 3 protein rescued E3L-minus VV replication in HeLa cells. In these studies, rescue by sigma 3 mutants correlated with their ability to bind dsRNA. Finally, vP112 was also able to rescue the replication of the IFN-sensitive virus vesicular stomatitis virus in a manner similar to that of wild-type VV. Together, these results suggest that the reovirus S4 gene can replace the VV E3L gene with respect to interference with the IFN-induced antiviral activity.
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PMID:Reversal of the interferon-sensitive phenotype of a vaccinia virus lacking E3L by expression of the reovirus S4 gene. 752 85


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