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)

Numerous targets are known for development of antiviral agents, and some significant successes have been achieved with nucleoside analogues. These are "activated" by phosphorylation by viral and/or host-cell nucleoside kinases, the final target being principally the viral polymerase. With latency of herpes viruses, the viral thymidine kinase may be the ultimate target. Less attention has been devoted to viral protein kinases as antiviral targets, largely because 5 years ago, these the study of such enzymes was considered "still in its infancy." In the interim, identification of viral and host-cell protein kinases involved in viral gene expression, and viral replication, has made impressive advances. In conjunction with current progress in development of specific inhibitors of cellular protein kinases, and the differences in sequence motifs between these and the viral enzymes, the latter are indeed attractive targets, as are also some host-cell protein kinases. Examples include, amongst others, the essential protein kinases of vaccinia virus; the nonsegmented negative-strand RNA viruses, all essentially dependent on host-cell kinases, e.g., protein kinase CK-II (casein kinase-II), for which good inhibitors, such as halogenated benzimidazoles and benzotriazoles, are known; herpes viruses, with emphasis on human cytomegalovirus, the UL97 gene of which codes for a protein kinase that, like viral thymidine kinases, "activates," by phosphorylation, a nonpeptide antiviral acyclonucleoside ganciclovir, an analogue of the antiherpes aciclovir. The latter, in turn, is active against animal cytomegaloviruses following phosphorylation by the products of their UL97 gene homologues. Attention is also directed to the antiviral activity of the cyclic phosphate of ganciclovir, a structural analogue of the second messenger cyclic GMP.
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PMID:Viral and host-cell protein kinases: enticing antiviral targets and relevance of nucleoside, and viral thymidine, kinases. 1045 9

Vascular gene transfer potentially offers new treatments for cardiovascular diseases. It can be used to overexpress therapeutically important proteins and correct genetic defects, and to test experimentally the effects of various genes in a local vascular compartment. Vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) gene transfers have improved blood flow and collateral development in ischaemic limb and myocardium. Promising therapeutic effects have been obtained in animal models of restenosis or vein-graft thickening with the transfer of genes coding for VEGF, nitric-oxide synthase, thymidine kinase, retinoblastoma, growth arrest homoeobox, tissue inhibitor of metalloproteinases, cyclin or cyclin-dependent kinase inhibitors, fas ligand and hirudin, and antisense oligonucleotides against transcription factors or cell-cycle regulatory proteins. First experiences of VEGF gene transfer and decoy oligonucleotides in human beings have been reported. However, further developments in gene-transfer vectors, gene-delivery techniques and identification of effective treatment genes will be required before the full therapeutic potential of gene therapy in cardiovascular disease can be assessed.
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PMID:Cardiovascular gene therapy. 1067 33

To clarify whether varicella-zoster virus (VZV) protein kinase (PK; ORF47) takes part in phosphorylation of anti-herpesvirus nucleosides, thymidine kinase (TK) deficient, and PK/TK double deficient recombinant VZV strains were isolated and their susceptibility, and that of wild type and PK-deficient strains to various nucleoside analogs was evaluated. The PK-deficient VZV strains showed a sensitivity equal to that of the wild type strain against all compounds tested, including ganciclovir. This indicates that PK is not involved in phosphorylation of the tested nucleosides in VZV-infected cells.
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PMID:Susceptibility of protein kinase (ORF47)-deficient varicella-zoster virus strains to anti-herpesvirus nucleosides. 1077 92

Vascular gene transfer potentially offers new treatments for cardiovascular diseases. It may be used to overexpress therapeutically important proteins and correct genetic defects, and to test experimentally the effects of various genes in a local vascular compartment. Vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) gene transfers have improved blood flow and collateral development in ischemic limb and myocardium. Promising therapeutic effects have been obtained in animal models of restenosis or vein-graft thickening with the transfer of genes coding for VEGF, nitric-oxide synthase, thymidine kinase, retinoblastoma, growth arrest homoeobox, tissue inhibitor of metalloproteinases, cyclin or cyclin-dependent kinase inhibitors, fas ligand and hirudin, and antisense oligonucleotides against transcription factors or cell-cycle regulatory proteins. First experiences of VEGF gene transfer and decoy oligonucleotides in human beings have been reported. However, further developments in gene transfer vectors, gene delivery techniques and identification of effective treatment genes will be required before the full therapeutic potential of gene therapy in cardiovascular disease can be assessed.
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PMID:[The status of gene therapy in cardiovascular medicine]. 1114 72

Several guanosine analogues, i.e. acyclovir (and its oral prodrug valaciclovir), penciclovir (in its oral prodrug form, famciclovir) and ganciclovir, are widely used for the treatment of herpesvirus (i.e. HSV-1, HSV-2, VZV and HCMV) infections. In recent years, several new guanosine analogues have been developed, including the 3-membered (cyclopropyl) sugar derivative A-5021 and the 6-membered D- and L-cyclohexenyl derivatives. Prominent features shared by all guanosine analogues are the following. They depend for their phosphorylation on the virus-encoded thymidine kinase (TK), which makes them particularly effective against those viruses (HSV-1, HSV-2 and VZV) that encoded for such TK. They are also active against HCMV, whether or not they are subject of phosphorylation by the HCMV-induced UL97 protein kinase. Their antiviral activity can be markedly potentiated by mycophenolic acid, an IMP dehydrogenase inhibitor, and they hold great promise, not only as antiviral agents for the treatment of herpesvirus infections, but also as antitumor agents for the combined gene therapy/chemotherapy of cancer, provided that (part of) the tumor cells have been transfected by the viral TK gene.
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PMID:Guanosine analogues as anti-herpesvirus agents. 1120 Feb 57

Here we show that human protein kinase C mu (PKC mu) activates the mitogen-activated protein kinase (MAPK). Transient expression of constitutive active PKC mu leads to an activation of Raf-1 kinase as demonstrated by in vitro phosphorylation of MAPK. PKC mu enhances transcriptional activity of a basal thymidine kinase promotor containing serum response elements (SREs) as shown by luciferase reporter gene assays. SRE driven gene activation by PKC mu is triggered by the Elk-1 ternary complex factor. PKC mu-mediated activation of SRE driven transcription can be inhibited by the MEK1 inhibitor PD98059. In contrast to the activation of the p42/ERK1 MAPK cascade, transient expression of constitutive active PKC mu does neither affect c-jun N-terminal kinase nor p38 MAPK.
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PMID:Protein kinase C mu selectively activates the mitogen-activated protein kinase (MAPK) p42 pathway. 1124 33

The overexpression of the cyclin-dependent kinase (CDK) inhibitor p21(Waf1) can inhibit cell proliferation, which is mediated by direct binding to CDK and proliferating-cell nuclear antigen. In this study, we demonstrated that human cytosolic thymidine kinase 1 (TK1) polypeptide can form a complex with p21(Waf1). The C-terminal domain of p21(Waf1) appeared to interact with the TK1 polypeptide, but, despite the inhibitory function of p21(Waf1), their association did not alter TK1 functional activity. However, overexpression of TK1 overcame p21(Waf1)-mediated growth suppression and blocked the association of CDK2 with p21(Waf1), suggesting that TK1 interferes with the inhibitory function of p21(Waf1). Based on these results, we here propose that the molecular function of p21(Waf1) in cells can be perturbed through its interaction with another cellular protein, TK1.
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PMID:Interaction of human thymidine kinase 1 with p21(Waf1). 1138 91

We used an autoimmune serum from a patient with discoid lupus erythematosus to clone a cDNA of 2808 base pairs. Its open reading frame of 2079 base pairs encodes a predicted polypeptide of 693 amino acids named CDA1 (cell division autoantigen-1). CDA1 has a predicted molecular mass of 79,430 Daltons and a pI of 4.26. The size of the cDNA is consistent with its estimated mRNA size. CDA1 comprises an N-terminal proline-rich domain, a central basic domain, and a C-terminal bipartite acidic domain. It has four putative nuclear localization signals and potential sites for phosphorylation by cAMP and cGMP-dependent kinases, protein kinase C, thymidine kinase, casein kinase II, and cyclin-dependent kinases (CDKs). CDA1 is phosphorylated in HeLa cells and by cyclin D1/CDK4, cyclin A/CDK2, and cyclin B/CDK1 in vitro. Its basic and acidic domains contain regions homologous to almost the entire human leukemia-associated SET protein. The same basic region is also homologous to nucleosome assembly proteins, testis TSPY protein, and an uncharacterized brain protein. CDA1 is present in the nuclear fraction of HeLa cells and localizes to the nucleus and nucleolus in HeLa cells transfected with CDA1 or its N terminus containing all four nuclear localization signals. Its acidic C terminus localizes mainly to the cytoplasm. CDA1 levels are low in serum-starved cells, increasing dramatically with serum stimulation. Expression of the CDA1 transgene, but not its N terminus, arrests HeLa cell growth, colony numbers, cell density, and bromodeoxyuridine uptake in a dose-dependent manner. The ability of CDA1 to arrest cell growth is abolished by mutation of the two CDK consensus phosphorylation sites. We propose that CDA1 is a negative regulator of cell growth and that its activity is regulated by its expression level and phosphorylation.
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PMID:SET-related cell division autoantigen-1 (CDA1) arrests cell growth. 1139 79

Alpha/beta interferons (IFN-alpha/beta) are potent, endogenous antiviral cytokines that suppress the replication of RNA and DNA viruses, including herpes simplex virus type 1 (HSV-1). The present study compared the efficacies of IFN-alpha/beta transgenes, including IFN-alpha1, -alpha4, -alpha5, -alpha6, -alpha9, and -beta, against HSV-1 infection. L929 cells transfected with the IFN-alpha/beta transgenes produced similar levels of IFN, as measured by bioassay and enzyme-linked immunosorbent assay. In addition, transfected cells were less susceptible to HSV-1 infection than were cells transfected with a plasmid vector control. The murine IFN-beta plasmid construct exhibited the greatest reduction, while the murine IFN-alpha5 transgene showed a modest inhibitory effect in viral titers recovered from the supernatants of transfected, infected L929 cultures. Consistent with this observation, the IFN-beta transgene antagonized viral transcript levels, including infected cell protein 27, thymidine kinase, and glycoprotein B, to a greater extent than did the IFN-alpha transgenes at 6 to 10 h postinfection as determined by real-time PCR. Cells transfected with the IFN-alpha4, IFN-alpha9, or IFN-beta transgenes showed the greatest reduction in viral protein expression relative to the other transfected cells, which was associated with increased STAT1 expression. The absence of the IFN-responsive protein kinase R (PKR) gene completely abrogated the antiviral induction by all IFN-alpha/beta against HSV-1. In the absence of RNase L, viral yields were increased 10-fold, but the antiviral effect of IFN was either unaffected or enhanced. These results suggest that the predominant IFN-mediated, antiviral pathway during HSV-1 infection taken by IFN-alpha/beta in L929 cells utilizes PKR.
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PMID:Differential effect of murine alpha/beta interferon transgenes on antagonization of herpes simplex virus type 1 replication. 1205 Mar 68

The C gamma and C alpha isoforms of the cAMP-dependent protein kinase (PKA) share 83% identity including all critical catalytic and substrate-binding residues defined to date. Compared to C alpha, C gamma has a different substrate specificity and a selective pseudosubstrate specificity, exhibiting inhibition by regulatory subunits, but not by the protein kinase inhibitor. In these studies, C gamma-mediated gene transcription regulation was compared with that of C alpha in four cell lines using transient transfection/dual luciferase assays. As compared to C gamma, C alpha more efficiently activated a cAMP-response element (CRE)-regulated fragment of the human alpha-glycoprotein hormone promoter which was coupled to a firefly luciferase reporter gene (pGH alpha-fluc). This occurred in Cos7, Y1, and Kin8 adrenal cells by 23-, 6.5-, and 1.4-fold, respectively. In contrast, C gamma, but not C alpha, activated the Sp1RE-regulated herpes simplex virus thymidine kinase promoter which was coupled to a Renilla luciferase reporter (pTK-rluc). In Sp1-deficient Sf9 cells, pGH alpha-fluc expression was maintained for both isoforms, but cotransfection with an Sp1 expression plasmid was necessary and sufficient for activation of pTK-rluc expression by C gamma. In all cell lines, cotransfection with a PDK1 expression plasmid enhanced the transcriptional activation of both C alpha and C gamma (1.5- to 3-fold), while a catalytically inactive PDK1 mutant (PDK.KD) did not. These results suggest that both C alpha and C gamma can activate CRE-responsive genes; however, C alpha does so with better efficiency than C gamma. In contrast to C alpha, C gamma activates transcription of genes containing pTK-like Sp1RE sites. Activation of different C subunit isoforms can provide a means to diversify cAMP-mediated transcription, possibly affecting cell phenotype.
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PMID:Differential transcriptional regulation by the alpha- and gamma-catalytic subunit isoforms of cAMP-dependent protein kinase. 1213 71


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