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)

Lobucavir (LBV) is a deoxyguanine nucleoside analog with broad-spectrum antiviral activity. LBV was previously shown to inhibit herpes simplex virus (HSV) DNA polymerase after phosphorylation by the HSV thymidine kinase. Here we determined the mechanism of action of LBV against human cytomegalovirus (HCMV). LBV inhibited HCMV DNA synthesis to a degree comparable to that of ganciclovir (GCV), a drug known to target the viral DNA polymerase. The expression of late proteins and RNA, dependent on viral DNA synthesis, was also inhibited by LBV. Immediate-early and early HCMV gene expression was unaffected, suggesting that LBV acts temporally coincident with HCMV DNA synthesis and not through cytotoxicity. In vitro, the triphosphate of LBV was a potent inhibitor of HCMV DNA polymerase with a Ki of 5 nM. LBV was phosphorylated to its triphosphate form intracellularly in both infected and uninfected cells, with phosphorylated metabolite levels two- to threefold higher in infected cells. GCV-resistant HCMV isolates, with deficient GCV phosphorylation due to mutations in the UL97 protein kinase, remained sensitive to LBV. Overall, these results suggest that LBV-triphosphate halts HCMV DNA replication by inhibiting the viral DNA polymerase and that LBV phosphorylation can occur in the absence of viral factors including the UL97 protein kinase. Furthermore, LBV may be effective in the treatment of GCV-resistant HCMV.
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PMID:Lobucavir is phosphorylated in human cytomegalovirus-infected and -uninfected cells and inhibits the viral DNA polymerase. 942 38

The N terminus of the R1 subunit of herpes simplex virus type 2 ribonucleotide reductase is believed to be a protein kinase domain mainly because the R1 protein was phosphorylated in a protein kinase assay on blot. Using Escherichia coli and adenovirus expression vectors to produce R1, we found that, whereas the reductase activity of both recombinant proteins was similar, efficient phosphorylation of R1 and casein in the presence of Mg2+ was obtained only with the R1 purified from eukaryotic cells. Phosphorylation of this R1, in solution or on blot, results mainly from the activity of casein kinase II (CKII), a co-purifying protein kinase. Labeling on blot occurs from CKII leakage off the membrane and its subsequent high affinity binding to in vivo CKII-phosphorylated R1. CKII target sites were mapped to an acidic serine-rich segment of the R1 N terminus. Improvement in purification of the R1 expressed in eukaryotic cells nearly completely abolished its phosphorylation potential. An extremely low level of phosphorylation observed in the presence of Mn2+ with the R1 produced in E. coli was probably due to an unidentified prokaryotic protein kinase. These results provide evidence that the herpes simplex virus type 2 R1 does not possess an intrinsic protein kinase activity.
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PMID:The R1 subunit of herpes simplex virus ribonucleotide reductase is a good substrate for host cell protein kinases but is not itself a protein kinase. 943 Jun 80

Herpes simplex virus 1 encodes a Fc receptor consisting of glycoproteins E (gE) and I (gI) and two protein kinases specified by UL13 and US3, respectively. We report the following: (i) Antibody to UL13 formed immune complexes containing gE and gI in addition to UL13 protein. Immune complexes formed by monoclonal antibody to gE, but not those formed by monoclonal antibody to gI, also contained the UL13 protein. This association may reflect direct interaction between gE and UL13 inasmuch as IgG in preimmune rabbit serum and an antiserum made against another viral protein which does not react with the UL13 protein directly also bound gE and UL13. (ii) In cells infected with the wild-type virus, gE formed two sharp bands and a diffuse, slower migrating band. The slower sharp band was undetectable, and the diffuse slower migrating forms of gE were diminished in lysates of cells infected with a mutant virus lacking the UL13 gene (DeltaUL13). (iii) Both gE and gI were labeled with 32Pi in cells infected with wild-type or the DeltaUL13 virus, but the labeling was significantly stronger in cells infected with the wild-type virus than in those infected with the DeltaUL13 virus. (iv) In an in vitro protein kinase assay, UL13 immunoprecipitated from cells infected with wild-type virus labeled gE in the presence of [gamma-32P]ATP. This activity was absent in precipitates from cells infected with DeltaUL13 virus. The labeled gE comigrated with the slower, sharp band of gE. (v) gI present in the UL13 immune complex was also phosphorylated in the in vitro kinase assay. (vi) The cytoplasmic domain of gE contains recognition sequences for phosphorylation by casein kinase II (CKII). Exogenous CKII phosphorylated gE in immune complexes from lysates of cells infected with the DeltaUL13 mutant or in immune complexes from lysates of cells infected with wild-type virus that had been heated to inactivate all endogenous kinase activity including that of UL13. In both instances, CKII phosphorylated gE in both the slow and fast migrating sharp bands. We conclude that UL13 physically associates with gE and mediates the phosphorylation of gE and gI. UL13 may also be a determinant in posttranslational processing of gE.
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PMID:UL13 protein kinase of herpes simplex virus 1 complexes with glycoprotein E and mediates the phosphorylation of the viral Fc receptor: glycoproteins E and I. 945 15

The translation elongation factor 1delta (EF-1delta) consists of two forms, a hypophosphorylated form (apparent Mr, 38,000) and a hyperphosphorylated form (apparent Mr, 40,000). Earlier Y. Kawaguchi, R. Bruni, and B. Roizman (J. Virol. 71:1019-1024, 1997) reported that whereas mock-infected cells accumulate the hypophosphorylated form, the hyperphosphorylated form of EF-1delta accumulates in cells infected with herpes simplex virus 1. We now report that the accumulation of the hyperphosphorylated EF-1delta is due to phosphorylation by U(L)13 protein kinase based on the following observations. (i) The relative amounts of hypo- and hyperphosphorylated EF-1delta in Vero cells infected with mutant virus lacking the U(L)13 gene could not be differentiated from those of mock-infected cells. In contrast, the hyperphosphorylated EF-1delta was the predominant form in Vero cells infected with wild-type viruses, a recombinant virus in which the deleted U(L)13 sequences were restored, or with a virus lacking the U(S)3 gene, which also encodes a protein kinase. (ii) The absence of the hyperphosphorylated EF-1delta in cells infected with the U(L)13 deletion mutant was not due to failure of posttranslational modification of infected-cell protein 22 (ICP22)/U(S)1.5 or of interaction with ICP0, inasmuch as preferential accumulation of hyperphosphorylated EF-1delta was observed in cells infected with viruses from which the genes encoding ICP22/U(S)1.5 or ICP0 had been deleted. (iii) Both forms of EF-1delta were labeled by 32Pi in vivo, but the prevalence of the hyperphosphorylated EF-1delta was dependent on the presence of the U(L)13 protein. (iv) EF-1delta immunoprecipitated from uninfected Vero cells was phosphorylated by U(L)13 precipitated by the anti-U(L)13 antibody from lysates of wild-type virus-infected cells, but not by complexes formed by the interaction of the U(L)13 antibody with lysates of cells infected with a mutant lacking the U(L)13 gene. This is the first evidence that a viral protein kinase targets a cellular protein. Together with evidence that ICP0 also interacts with EF-1delta reported in the paper cited above, these data indicate that herpes simplex virus 1 has evolved a complex strategy for optimization of infected-cell protein synthesis.
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PMID:Eukaryotic elongation factor 1delta is hyperphosphorylated by the protein kinase encoded by the U(L)13 gene of herpes simplex virus 1. 949 21

Several publications have attested to the ability of herpes simplex viruses to protect cells against apoptosis. We investigated the ability of the virus to protect cells in continuous cultivation from apoptosis induced by the virus itself, and by other known inducers such as exposure to the tumor necrosis factor alpha (TNFalpha), antibody to Fas, C2-ceramide, osmotic shock (sorbitol), and thermal shock. The salient features of the results were that the virus was able to protect cells against apoptosis by all of the agents tested, and that apoptosis induced by the virus was a very early event that did not require de novo expression of viral genes. However, these events were cell-type specific. Thus: (i) The cell lines tested exhibited fragmented chromosomal DNA following infection with a virus lacking functional alpha4 and US3 genes encoding the major regulatory protein and a viral protein kinase, respectively, but not by wild-type virus. (ii) Wild-type virus protected subconfluent SK-N-SH but not HeLa cells against induction of apoptosis by anti-Fas antibody, TNFalpha, C2-ceramide, and thermal shock. Confluent SK-N-SH cells were not protected from osmotic shock-induced apoptosis by wild-type infection. (iii) Wild-type virus protected SK-N-SH but not HeLa cells against induction of apoptosis by sorbitol, anti-Fas antibody, or TNFalpha and C2-ceramide. (iv) Mutant HSV-1(HFEM)tsB7 at the nonpermissive temperature infects cells but the DNA is not released from capsids, and therefore viral gene expression is restricted to the function of viral proteins introduced into the cell along with the capsid containing the viral DNA. HSV-1(HFEM)tsB7 induced apoptosis in Vero cells but not in SK-N-SH cells infected and maintained at 39.5 degrees C. (v) Tests of two caspase inhibitors showed that they blocked apoptosis induced by C2-ceramide and sorbitol, but were not able to block apoptosis induced by the virus lacking functional alpha4 and US3 genes. We conclude that HSV-1 triggers apoptosis at multiple metabolic checkpoints and in turn has evolved mechanisms to block apoptosis at each point and that some of the pathways of induction are shared with exogenous inducers tested in this study whereas others are not.
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PMID:Herpes simplex virus 1 induces and blocks apoptosis at multiple steps during infection and protects cells from exogenous inducers in a cell-type-dependent manner. 952 Apr 70

One supposes that herpes simplex virus US3 gene product possessing serine/threonine protein kinase activity is a cytoplasmic enzyme. To determine its subcellular localization during viral replication we prepared an antiserum to a synthetic oligopeptide corresponding to the N-terminal region of the US3 protein of HSV type 2 strain 186. The US3 protein first appeared in the cytoplasm of infected cell at 4 h postinfection but strong fluorescence was detected in the nuclei at 8 h postinfection. At 12 h postinfection fluorescence was mainly detected in the cytoplasm, again. Further, the US3 protein expressed alone was widely distributed throughout the cell, indicating that the US3 protein by itself can be localized in the nuclei even in the absence of any other viral proteins. These observations suggest that the HSV-2 US3 protein kinase may function not only in the cytoplasm but also in the nuclei.
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PMID:Subcellular localization of the US3 protein kinase of herpes simplex virus type 2. 957 61

The modulation of motor behavior by protein kinase C (PKC) signaling pathways in nigrostriatal neurons was examined by using a genetic intervention approach. Herpes simplex virus type 1 (HSV-1) vectors that encode a catalytic domain of rat PKCbetaII (PkcDelta) were developed. PkcDelta exhibited a constitutively active protein kinase activity with a substrate specificity similar to that of rat brain PKC. As demonstrated in cultured sympathetic neurons, PkcDelta caused a long-lasting, activation-dependent increase in neurotransmitter release. In the rat brain, microinjection of HSV-1 vectors that contain the tyrosine hydroxylase promoter targeted expression to dopaminergic nigrostriatal neurons. Expression of pkcDelta in a small percentage of nigrostriatal neurons (approximately 0.1-2%) was sufficient to produce a long-term (>/=1 month) change in apomorphine-induced rotational behavior. Nigrostriatal neurons were the only catecholaminergic neurons that contained PkcDelta, and the amount of rotational behavior was correlated with the number of affected nigrostriatal neurons. The change in apomorphine-induced rotational behavior was blocked by a dopamine receptor antagonist (fluphenazine). D2-like dopamine receptor density was increased in those regions of the striatum innervated by the affected nigrostriatal neurons. Therefore, this strategy enabled the demonstration that a PKC pathway or PKC pathways in nigrostriatal neurons modulate apomorphine-induced rotational behavior, and altered dopaminergic transmission from nigrostriatal neurons appears to be the affected neuronal physiology responsible for the change in rotational behavior.
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PMID:Modulation of rat rotational behavior by direct gene transfer of constitutively active protein kinase C into nigrostriatal neurons. 959 92

The interferon (IFN)-induced cellular antiviral response is the first line of defense against viral infection within an animal host. In order to establish a productive infection, eukaryotic viruses must first overcome the IFN-induced blocks imposed on viral replication. The double-stranded RNA-activated protein kinase (PKR) is a key component mediating the antiviral actions of IFN. This IFN-induced protein kinase can restrict viral replication through its ability to phosphorylate the protein synthesis initiation factor eukaryotic initiation factor-2 alpha-subunit and reduce levels of viral protein synthesis. Viruses, therefore, must block the function of PKR in order to avoid these deleterious antiviral effects associated with PKR activity. Indeed, many viruses have developed effective measures to repress PKR activity during infection. This review will focus primarily on an overview of the different molecular mechanisms employed by these viruses to meet a common goal: the inhibition of PKR function, uncompromised viral protein synthesis, and unrestricted virus replication. The past few years have seen exciting new advances in this area. Rather unexpectedly, this area of research has benefited from the use of the yeast system to study PKR. Other recent advances include studies on PKR regulation by the herpes simplex viruses and data from our laboratory on the medically important hepatitis C viruses. We speculate that IFN is ineffective as a therapeutic agent against hepatitis C virus because the virus can effectively repress PKR function. Finally, we will discuss briefly the future directions of this PKR field.
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PMID:Molecular mechanisms of interferon resistance mediated by viral-directed inhibition of PKR, the interferon-induced protein kinase. 959 28

Canine herpesvirus (CHV) is an alpha-herpesvirus of limited pathogenicity in healthy adult dogs and infectivity of the virus appears to be largely limited to cells of canine origin. CHV's low virulence and species specificity make it an attractive candidate for a recombinant vaccine vector to protect dogs against a variety of pathogens. As part of the analysis of the CHV genome, the authors determined the complete nucleotide sequence of the CHV US region as well as portions of the flanking inverted repeats. Seven full open reading frames (ORFs) encoding proteins larger than 100 amino acids were identified within, or partially within the CHV US: cUS2, cUS3, cUS4, cUS6, cUS7, cUS8 and cUS9; which are homologs of the herpes simplex virus type-1 US2; protein kinase; gG, gD, gI, gE; and US9 genes, respectively. An eighth ORF was identified in the inverted repeat region, cIR6, a homolog of the equine herpesvirus type-1 IR6 gene. The authors identified and mapped most of the major transcripts for the predicted CHV US ORFs by Northern analysis.
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PMID:Genomic organization of the canine herpesvirus US region. 962 Feb 7

Several observations indicate that late-G1/S-phase-specific cellular functions may be required for herpes simplex virus (HSV) replication: (i) certain mutant HSV strains are replication impaired during infection of cells in the G0/G1 but not in the G1/S phase of the cell cycle, (ii) several late-G1/S-phase-specific cellular proteins and functions are induced during infection, and (iii) the activity of a cellular protein essential for expression of viral immediate-early (IE) genes, HCF, is normally required during the late G1/S phase of the cell cycle. To test the hypothesis that late-G1/S-phase-specific cellular functions are necessary for HSV replication, HEL or Vero cells were infected in the presence of the cell cycle inhibitors roscovitine (Rosco) and olomoucine (Olo). Both drugs inhibit cyclin-dependent kinase 1 (cdk-1) and cdk-2 (required for cell cycle progression into the late G1/S phase) and cdk-5 (inactive in cycling cells) but not cdk-4 or cdk-6 (active at early G1). We found that HSV replication was inhibited by Rosco and Olo but not by lovastatin (a cell cycle inhibitor that does not inhibit cdk activity), staurosporine (a broad-spectrum protein serine-threonine kinase inhibitor), PD98059 (an inhibitor specific for erk-1 and -2) or iso-Olo (a structural isomer of Olo that does not inhibit cdk activity). The concentrations of Rosco and Olo required to inhibit cell cycle progression and viral replication in both HEL and Vero cells were similar. Inhibition of viral replication was found not to be mediated by drug-induced cytotoxicity. Efforts to isolate Rosco- or Olo-resistant HSV mutants were unsuccessful, indicating that these drugs do not act by inhibiting a single viral target. Viral DNA replication and accumulation of IE and early viral RNAs were inhibited in the presence of cell cycle-inhibitory concentrations of Rosco or Olo. We therefore conclude that one or more cdks active from late G1 onward or inactive in nonneuronal cells are required for accumulation of HSV transcripts, viral DNA replication, and production of infectious virus.
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PMID:Requirement for cellular cyclin-dependent kinases in herpes simplex virus replication and transcription. 962 Oct 21


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