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)

The molecular basis for cytomegalovirus drug resistance against currently used antivirals comprises two genetic loci. In the case of ganciclovir, mutations in both the UL97 protein kinase and UL64 DNA polymerase can lead to resistance, whereas for cidofovir and foscarnet only mutations in UL54 give rise to resistance. Clinically, resistance strains of cytomegalovirus appear after prolonged periods of antiviral therapy especially when treatment has been interrupted or is at sub-optimal doses. Knowledge of the replication dynamics of cytomegalovirus in vivo can be used to predict the virologic course of patients who develop resistance virus. Using such models, a good agreement between experimentally determined viral load and resistance patterns is observed.
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PMID:Progress in understanding cytomegalovirus drug resistance. 1139 58

Ultraviolet light (UV), ionizing-radiation or alkylating agents are known as carcinogens, mostly because of their ability to damage DNA directly. However, they may also play a diverse role in activating the signal pathways and altering the gene expression. We have shown previously that N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) of 0.2 microM can increase the transcription of DNA polymerase-beta gene, which has a cyclic AMP response element (CRE) motif in its promoter. Using the CRE report vector, we show here, such treatment can stimulate the CRE-driven gene expression by approximately 1.5-fold compared with control. Consistent with it, the proportion of ser-133 phosphorylated CRE binding protein (CREB), the related transcription factor was 2.08-fold higher versus control in vero cells after 60 min of MNNG treatment. Although CREB has many putative kinases for its phosphorylation, such as p38 mitogen-activated protein kinase (p38 MAPK), Ca(2+)/calmodulin-dependent protein kinase Pi (CaMK Pi) and protein kinase C (PKC), we found the protein kinase A (PKA) was activated and its activation peaked when cells were treated for 60 min (with arbitrary activity unit of 11.03+/-2.80 and 0.86+/-0.43 in treatment and control, respectively), this phasic character was similar to that of the CREB phosphorylation. We also determined the intracellular cyclic AMP (cAMP) levels and it was found that the cAMP concentration was elevated after 60 min treatment (1.53-fold higher). However, to our surprise, we did not find any accompanying cAMP elevation in cells treated by MNNG for 30 min, in which PKA was activated significantly. These findings, together with other observations, suggest that cAMP-PKA-CREB signaling pathway mediates the low concentration MNNG induced pol-beta expression. In addition to elevated cAMP, there might exist a cAMP-independent PKA activation manner in this course.
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PMID:Low concentration N-methyl-N'-nitro-N-nitrosoguanidine activates DNA polymerase-beta expression via cyclic-AMP-protein kinase A-cAMP response element binding protein pathway. 1140 82

Chilo iridescent virus (CIV), the type species of the genus Iridovirus, a member of the Iridoviridae family, is highly pathogenic for a variety of insect larvae. The virions contain a single linear ds DNA molecule that is circularly permuted and terminally redundant. The coding capacity and strategy of the CIV genome was elucidated by the analysis of the complete DNA nucleotide sequence of the viral genome (212,482 bp) using cycle sequencing by primer walking technology. Both DNA strands were sequenced independently and the average redundancy for each nucleotide was found to be 1.85. The base composition of the viral genomic DNA sequence was found to be 71.37% A+T and 28.63% G+C. The CIV genome contains 468 open reading frames (ORFs). The size of the individual viral gene products ranges between 40 and 2432 amino acids. The analysis of the coding capacity of the CIV genome revealed that 50% (234 ORFs) of all identified ORFs were nonoverlapping. The comparison of the deduced amino acid sequences to entries in protein data banks led to the identification of several genes with significant homologies, such as the two major subunits of the DNA-dependent RNA polymerase, DNA polymerase, protein kinase, thymidine and thymidylate kinase, thymidylate synthase, ribonucleoside-diphosphate reductase, major capsid protein, and others. The highest homologies were detected between putative viral gene products of CIV and lymphocystis disease virus of fish (LCDV). Although many CIV putative gene products showed significant homologies to the corresponding viral proteins of LCDV, no colinearity was detected when the coding strategies of the CIV and LCDV-1 were compared to each other. An intriguing result was the detection of a viral peptide of 53 amino acid residues (ORF 160L) showing high homology (identity/similarity: 60.0%/30.0%) to sillucin, an antibiotic peptide encoded by Rhizomucor pusillus. Iridovirus homologs of cellular genes possess particular implications for the molecular evolution of large DNA viruses.
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PMID:Analysis of the first complete DNA sequence of an invertebrate iridovirus: coding strategy of the genome of Chilo iridescent virus. 1144 71

Cancer cells are characterized by limitless proliferative autonomy and immunity to inhibitory and apoptotic signals, thus ensuring growth and metastasis [1]. Epidemiological studies have long implicated human papillomavirus (HPV) as a pathogenic agent in cervical cancer. Progress in cancer research now provides an understanding of how these characteristics are achieved by the interaction of HPV proteins with the cell cycle machinery. Expression of oncoproteins E7 and E6 induces immortalization of cells through their inhibitory effects on tumor suppressor proteins pRb and p53, respectively. Undermining of pRb's growth-inhibitory role with release of E2F transcription factors renders the cells independent of mitogenic stimuli. The abundance of growth transcription factors grants limitless proliferative potential by allowing expression of products such as cyclins A, E, and B, dihydrofolate reductase, and DNA polymerase which fuel the various stages of the cell cycle. There is subsequent disruption of both the G1-S and G2-M cell cycle checkpoints. Overexpression of cyclin E results in chromosomal instability and possible unmasking of genetic mutations, allowing disease progression. Cyclin A grants anchorage-independent growth, facilitating tissue invasion and tumor spread. Apoptotic and growth-inhibitory mechanisms are also evaded. p53 is degraded by E6 and its own downstream protein mdm2. Its other downstream protein, p21 is rendered ineffective against cyclin-cyclin-dependent kinase units by E7, as is p27. The understanding of the molecular pathology of disease will provide us with the ability to prognosticate and treat patients more effectively.
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PMID:Cell cycle aberrations in the pathogenesis of squamous cell carcinoma of the uterine cervix. 1153 Dec 73

Earlier studies have shown that cdc2 kinase is activated during herpes simplex virus 1 infection and that its activity is enhanced late in infection even though the levels of cyclin A and B are decreased below levels of detection. Furthermore, activation of cdc2 requires the presence of infected cell protein no. 22 and the U(L)13 protein kinase, the same gene products required for optimal expression of a subset of late genes exemplified by U(S)11, U(L)38, and U(L)41. The possibility that the activation of cdc2 and expression of this subset may be connected emerged from the observation that dominant negative cdc2 specifically blocked the expression of U(S)11 protein in cells infected and expressing dominant negative cdc2. Here we report that in the course of searching for a putative cognate partner for cdc2 that may have replaced cyclins A and B, we noted that the DNA polymerase processivity factor encoded by the U(L)42 gene contains a degenerate cyclin box and has been reported to be structurally related to proliferating cell nuclear antigen, which also binds cdk2. Consistent with this finding, we report that (i) U(L)42 is able to physically interact with cdc2 at both the amino-terminal and carboxyl-terminal domains, (ii) the carboxyl-terminal domain of U(L)42 can be phosphorylated by cdc2, (iii) immunoprecipitates obtained with anti U(L)42 antibody contained a roscovitine-sensitive kinase activity, (iv) kinase activity associated with U(L)42 could be immunodepleted by antibody to cdc2, and (v) U(L)42 transfected into cells associates with a nocodazole-enhanced kinase. We conclude that U(L)42 can associate with cdc2 and that the kinase activity has the characteristic traits of cdc2 kinase.
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PMID:cdc2 cyclin-dependent kinase binds and phosphorylates herpes simplex virus 1 U(L)42 DNA synthesis processivity factor. 1158 1

After serial passage in the presence of increasing concentrations of ganciclovir (GCV) in vitro, a human herpesvirus-6 (HHV-6) mutant exhibiting a decreased sensitivity to the drug was isolated. Analysis of drug susceptibility showed that the IC(50) of this mutant was 24-, 52- and 3-fold higher than that of the wild-type (wt) IC(50) in the case of GCV, cidofovir and foscarnet, respectively. Genotypic analysis showed two single nucleotide changes as compared to the wild-type: an A-->G substitution of the U69 protein kinase (PK) gene resulted in an M(318)V amino acid substitution and the other change, located in the C-terminal part of the U38 gene, resulted in an A(961)V amino acid substitution within the DNA polymerase. The M(318)V change was located within the consensus sequence DISPMN of the putative catalytic domain VI of the PK. This change was homologous to the M(460)V and M(460)I changes that had been reported previously within the consensus sequence DITPMN of the human cytomegalovirus (HCMV) UL97 PK and associated with the resistance of HCMV to GCV. The M(318)V change was also detected by PCR in HHV-6-infected PBMCs from an AIDS patient who had been treated with GCV for a long period of time and exhibited a clinically GCV-resistant HCMV infection. These findings provide strong circumstantial evidence that the M(318)V change of the PK gene is associated with resistance to GCV and raise the question of cross resistance to this drug among different betaherpesviruses.
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PMID:Selection of the same mutation in the U69 protein kinase gene of human herpesvirus-6 after prolonged exposure to ganciclovir in vitro and in vivo. 1160 88

A member of the family of L-riboside benzimidazole compounds, 1263W94, was shown recently to inhibit replication of Epstein-Barr virus (EBV) (V. L. Zacny, E. Gershburg, M. G. Davis, K. K. Biron, and J. S. Pagano, J. Virol. 73:7271-7277, 1999). In the present report the effect of 1263W94 on the phosphorylation pattern of the EBV DNA polymerase processivity factor, EA-D, during viral reactivation in latently EBV-infected Akata cells is analyzed. This pattern specifically changes with progression of cytolytic infection. In the presence of 1263W94 the appearance of the hyperphosphorylated form of EA-D is mainly affected. Next, coexpression of the cloned EBV-encoded protein kinase (EBV PK), BGLF4, with EA-D demonstrated the ability of EBV PK to phosphorylate EA-D to its hyperphosphorylated form in transient assays. However, the phosphorylation of EA-D was not directly inhibited by 1263W94 in these coexpression assays. The results indicate that the EBV PK appears to be responsible for the hyperphosphorylation of EA-D, imply that the phosphorylation status of EA-D is important for viral replication, and suggest that 1263W94 acts at a level other than direct inhibition of EA-D phosphorylation by EBV PK.
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PMID:Phosphorylation of the Epstein-Barr virus (EBV) DNA polymerase processivity factor EA-D by the EBV-encoded protein kinase and effects of the L-riboside benzimidazole 1263W94. 1177 75

While the treatment of herpes simplex virus with acyclovir and similar nucleoside analogues was one of the first success stories in antiviral chemotherapy, substantial unmet medical needs remain for herpesvirus diseases. In particular, the increasing numbers of immunosuppressed people due to AIDS, transplantation, cancer and aging has driven the need for improved antivirals to treat diseases caused by human cytomegalovirus (HCMV). Currently available drugs for the treatment of HCMV diseases are less than ideal agents due to issues of toxicity, modest efficacy and poor oral bioavailability. High throughput screening of large compound collections for inhibitors of specific viral enzymes or inhibition of viral growth in cell culture have identified a number of new HCMV inhibitors at several pharmaceutical companies. These compounds act by inhibition of novel molecular targets such as the viral protein kinase, viral protease and viral proteins involved in DNA cleavage/packaging. In addition, novel non-nucleoside inhibitors of the herpesvirus DNA polymerase have recently been described. This review will summarise some of these research efforts and will focus on non-nucleoside compounds that directly inhibit a viral process.
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PMID:Non-nucleoside inhibitors of herpesviruses. 1198 42

Benzimidazole nucleosides have been shown to be potent inhibitors of human cytomegalovirus (HCMV) replication in vitro. As part of the exploration of structure-activity relationships within this series, we synthesized the 2-isopropylamino derivative (3322W93) of 1H-beta-D-ribofuranoside-2-bromo-5,6-dichlorobenzimidazole (BDCRB) and the biologically unnatural L-sugars corresponding to both compounds. One of the L derivatives, 1H-beta-L-ribofuranoside-2-isopropylamino-5,6-dichlorobenzimidazole (1263W94), showed significant antiviral potency in vitro against both laboratory HCMV strains and clinical HCMV isolates, including those resistant to ganciclovir (GCV), foscarnet, and BDCRB. 1263W94 inhibited viral replication in a dose-dependent manner, with a mean 50% inhibitory concentration (IC(50)) of 0.12 +/- 0.01 microM compared to a mean IC(50) for GCV of 0.53 +/- 0.04 microM, as measured by a multicycle DNA hybridization assay. In a single replication cycle, 1263W94 treatment reduced viral DNA synthesis, as well as overall virus yield. HCMV mutants resistant to 1263W94 were isolated, establishing that the target of 1263W94 was a viral gene product. The resistance mutation was mapped to the UL97 open reading frame. The pUL97 protein kinase was strongly inhibited by 1263W94, with 50% inhibition occurring at 3 nM. Although HCMV DNA synthesis was inhibited by 1263W94, the inhibition was not mediated by the inhibition of viral DNA polymerase. The parent benzimidazole D-riboside BDCRB inhibits viral DNA maturation and processing, whereas 1263W94 does not. The mechanism of the antiviral effect of L-riboside 1263W94 is thus distinct from those of GCV and of BDCRB. In summary, 1263W94 inhibits viral replication by a novel mechanism that is not yet completely understood.
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PMID:Potent and selective inhibition of human cytomegalovirus replication by 1263W94, a benzimidazole L-riboside with a unique mode of action. 1212 6

DNA polymerase alpha-primase (pol-prim) is a heterotetramer with DNA polymerase and primase activities. The polymerase (p180) and primase (p48 and p58) subunits synthesize primers and extend them, but the function of the remaining subunit (p68) is poorly understood. Genetic studies in yeast suggested an essential role for the p68 ortholog in early S phase prior to the hydroxyurea-sensitive step, possibly a regulatory role in initiation of DNA replication, but found no evidence for an essential function of p68 later in S phase. To investigate whether the human p68 subunit has an essential role in DNA replication, we examined the ability of a purified trimeric human pol-prim lacking p68 to initiate simian virus 40 DNA replication in vitro and to synthesize and elongate primers on single-stranded DNA in the presence of T antigen and replication protein A (RPA). Both activities of trimeric pol-prim were defective, but activity was recovered upon addition of separately purified p68. Phosphorylation of p68 by cyclin A-dependent protein kinase also inhibited both activities of pol-prim. The data strongly suggest that the p68 subunit is required for priming activity of pol-prim in the presence of RPA and T antigen, both during initiation at the origin and during lagging strand replication.
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PMID:Role of the p68 subunit of human DNA polymerase alpha-primase in simian virus 40 DNA replication. 1213 79


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