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Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The current state of knowledge concerning the biochemical transformation by Herpes Simplex virus (HSV) of mammalian cells lacking the enzyme thymidine kinase (TK) is reviewed. Transformation of thymidine kinase negative mouse cells (LTK-) to the TK+ phenotype by ultraviolet light-inactivated HSV preparations depends both on the irradiation dose and on the multiplicity of infection. Once stably associated with the transformed cell, the HSV thymidine kinase appears to be regulated differently than the cellular enzyme: HSV TK activity is maximal in stationary cells, whereas cellular TK activity is maximal during the S-pphase of growing cells. Furthermore, infection with an HSV TK- mutant virus leads to the induction of TK activity in HSV TK+ cells, but not in normal TK+ cells. Recent studies indicate that in addition to the TK gene, at least one other HSV gene, perhaps a structural antigen of the virion, is also transferred to TK- cells. This is consistent with the finding that a clone of HSV TK+ cells harbors approximately five copies per cell of 23 per cent of the HSV genome.
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PMID:Thymidine kinase gene transfer by herpes simplex virus. 18 68

VP16 (also called Vmw65 and alpha TIF) is a structural protein of herpes simplex virus type 1 (HSV-1) that trans-induces HSV-1 immediate-early gene transcription. This report describes an HSV-1 VP16 deletion mutant that was constructed and propagated in a cell line transformed with a VP16 expression vector. The VP16 deletion mutant replicated like wild-type HSV-1 during infection of the VP16-expressing cell line. Deletion mutant virions propagated in this cell line contained wild-type, cell-derived VP16 protein that was recruited during virion assembly and was functional for immediate-early gene trans-induction. The mutant failed to replicate during subsequent infection of cells that do not express VP16, as determined in plaque assays and single-step replication assays. The deletion mutant induced nearly normal levels of viral DNA synthesis and capsid production during these infections, but it induced slightly lower levels of viral DNA encapsidation and appeared by transmission electron microscopy to be defective in further steps of virion maturation. A genetic revertant of the deletion mutant that was restored for VP16-coding sequences exhibited fully wild-type replication properties in both VP16-expressing and nonexpressing cells. The absence of VP16 protein synthesis at late times of HSV-1 infection prevents the production of infectious progeny virus and correlates with a profound defect in HSV-1 particle assembly.
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PMID:Deletion of the VP16 open reading frame of herpes simplex virus type 1. 130 45

Herpes simplex virus type 1 (HSV-1) infection induces expression of the human immunodeficiency virus type 1 (HIV-1) provirus in the chronically infected T-cell line ACH-2. The HSV-1-mediated induction correlates with the appearance of two NF-kappa B-specific proteins of 55 and 85 kDa in the nucleus and with the binding of 50-kDa nuclear protein to the LBP-1 binding site of the untranslated leader sequence of the HIV-1 long terminal repeat. The HSV-1-induced LBP-1 binding protein, designated HLP-1, is present exclusively in HSV-1-infected, but not in phorbol-12-myristate-13-acetate- or tumor necrosis factor alpha-treated ACH-2 cells. Both the NF-kappa B and LBP-1 target sequences, when inserted either alone or together 5' of a heterologous minimal promoter (thymidine kinase), confer inducibility by HSV-1 infection in a transient transfection assay. Thus, it appears that the HSV-1-mediated activation of HIV-1 provirus is brought about by the binding of both NF-kappa B and HLP-1 specific proteins to two distinct regions of HIV-1 long terminal repeat.
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PMID:Herpes simplex virus type 1-mediated induction of human immunodeficiency virus type 1 provirus correlates with binding of nuclear proteins to the NF-kappa B enhancer and leader sequence. 131 71

A virion protein of herpes simplex virus type-1, called Vmw65, alpha TIF or VP16, interacts with cellular transcription factors to transactivate immediate early viral genes. We have cloned and determined the nucleotide sequence of the gene encoding the homologous protein in bovine herpesvirus 1 (BHV-1). The amino acid sequence of the BHV-1 protein is similar to that of alpha TIF, except in the C-terminal one-third of the protein. Since the ability of alpha TIF to activate transcription is dependent on this region, our results suggest that the BHV-1 homologue either does not act as a transactivator or activates genes by a different mechanism.
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PMID:Sequences of the bovine herpesvirus 1 homologue of herpes simplex virus type-1 alpha-trans-inducing factor (UL48). 132 63

Varicella-Zoster virus (VZV) is a neurotropic alphaherpes virus closely related to herpes simplex virus (HSV). However, unlike its close relative HSV, VZV lacks a functional alpha-TIF (alpha-gene transinducing factor) that activates the transcription of immediate early genes during the initial events of the virus life cycle. Hence, in the absence of a functional alpha-TIF, the mechanism triggering the expression of immediate early genes in VZV at present remains unclear. Accumulating evidence indicates that the gene product of the putative immediate early gene ORF62 (IE62) plays a pivotal role in activating VZV genes of all three putative kinetic classes, namely immediate early (alpha), early (beta), and late (gamma) classes of VZV genes. In the present study, we show that IE62 can positively autoregulate its cognate promoter using a transient transfection assay, both in lymphocytes and in neural cells. In the same system, we can also demonstrate activation of the VZV IE62 promoter by HSV ICP4. By deletion analysis and oligonucleotide-directed site-specific mutagenesis we have localized specific regions in the IE62 promoter/upstream sequences that mediate inducibility by IE62 and HSV ICP4, and provide evidence that this promoter activation by these two proteins may be through different mechanisms. These data, taken together with the recent demonstration of the presence of IE62 in the VZ virion tegument (Kinchington, P.R., Hoagland, J.K., Arvin, A.M., Ruyechan, W.T., and Hay, J. 1992. J. Virol. 66, 359-366) provides a possible mechanism by which the triggering of VZV gene expression occurs in the absence of a functional alpha-TIF protein.
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PMID:The varicella-zoster virus immediate early protein, IE62, can positively regulate its cognate promoter. 132 24

Heterologous viruses have been examined for their ability to accelerate the course of infection with the human immunodeficiency virus (HIV) type 1. In this study, ACH-2 cells persistently infected with HIV-1 exhibited augmented HIV-1 replication as a result of superinfection with herpes simplex virus (HSV) type 1. Using HSV-1 mutants with deletions in the genes encoding immediate-early proteins ICP0, ICP4, and ICP27, it was found that ICP0 and ICP27, but not ICP4, were essential for up-regulation of HIV replication. Northern blot analysis showed that this activation of HIV was characterized by an initial rise in the level of the small, subgenomic (2.0 and 4.3 kb) mRNA species, followed by an increase in the level of unspliced genomic (9.2 kb) mRNA. Such a shift in transcriptional phase recapitulates the early-to-late transition seen in single-step growth curves of acute HIV-1 infection. Thus, HSV can activate HIV-1 from latency in ACH-2 cells, this activation of HIV is independent of productive HSV replication since the delta ICP4 deletion mutant is replication-incompetent, and this activation is evident as an increase in the steady-state levels of HIV transcripts.
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PMID:Activation of human immunodeficiency virus by herpes simplex virus. 135 37

Homeo domain proteins exhibit distinct biological functions with specificities that cannot be predicted by their sequence specificities for binding DNA. Recognition of the surface of the Oct-1 POU homeo domain provides a general model for the contribution of selective protein-protein interactions to the functional specificity of the homeo domain family of factors. The assembly of Oct-1 into a multiprotein complex on the herpes simplex virus alpha/IE enhancer is specified by the interactions of its homeo domain with ancillary factors. This complex (C1 complex) is composed of the viral alpha TIF protein (VP16), Oct-1, and one additional cellular component, the C1 factor. Variants of the Oct-1 POU homeo domain were generated by site-directed mutagenesis, which altered the residues predicted to form the exposed surface of the domain-DNA complex. Proteins with single amino acid substitutions on the surface of either helix 1 or 2 of the Oct-1 POU homeo domain had decreased abilities to form the C1 complex. The behavior of these mutants in a cooperative DNA-binding assay with alpha TIF suggested that the Oct-1 POU homeo domain is principally recognized by alpha TIF in the C1 complex. The preferential recognition of Oct-1 over the closely related Oct-2 protein is critically influenced by a single residue on the surface of helix 1 because the introduction of this residue into the Oct-2 POU homeo domain significantly enhanced its ability to form a C1 complex.
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PMID:Recognition of the surface of a homeo domain protein. 135 55

In herpes simplex virus 1, the five alpha genes are induced by alpha-transinducing factor (alpha TIF; VP16), a virion protein, acting in concert with Oct-1 and other cellular proteins on a cis-acting site in the promoter domain of alpha genes. Because alpha TIF is an essential virion protein, its function as an inducer can best be evaluated only by mutating the cis-acting site. Earlier we reported on a series of 17 mutations in and around the cis-acting site of a 275-bp alpha 27 promoter fused to a reporter gene and recombined into the viral genome. These recombinant viruses were tested in Vero cells in the presence of cycloheximide, and we demonstrated that mutations in the sequence required for Oct-1 binding abolished transactivation whereas mutations in the alpha TIF-dependent GARAT sequence decreased but did not abolish transactivation. We now report that (i) in limited-passage human embryonic lung cells, alpha gene expression from promoters mutated in the GARAT sequences is often higher and more variable than in Vero cells, (ii) in the absence of cycloheximide, the mutant viruses show less significant impairment of reporter gene expression, (iii) Oct-1 can bind either to the overlapping octamer element or to various TAATGARAT sequences with differing degrees of binding strength and these relative binding levels correlate well with levels of gene expression observed in infected cells, (iv) in the cis-acting site upstream of the alpha 4 gene, no degenerate overlapping Oct-1 sequence exists, and therefore in this instance Oct-1 must be binding directly to the TAATGARAT sequence, (v) extension of the alpha 27 promoter by an additional 1,334 bp results in much higher expression of the reporter gene as a result of additional upstream cis-acting sites, and (vi) obliteration of the most proximal Oct-1 binding element within the 275-bp promoter dramatically reduces gene expression even in the presence of the additional upstream cis-acting sites.
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PMID:Role of alpha-transinducing factor (VP16) in the induction of alpha genes within the context of viral genomes. 164 82

Previous studies have shown that at least three polypeptides of 43, 39 and 38 kDa are translated from separate AUG codons of the thymidine kinase (TK) encoding mRNA of herpes simplex virus type 1. In addition, small tk-specific transcripts initiated within the tk coding region were observed. However, functional activity of these three proteins and their role in establishing of the TK+ cell phenotype is not yet clear. In order to locate the 5' boundary of the gene encoding functionally active TK, we constructed a set of deletion mutants with truncated 5' ends and examined their ability to provide a TK+ phenotype after microinjection into nuclei of LTK- cells. The results demonstrate that nucleotide sequences upstream from the second ATG codon can be removed without affecting the TK+ phenotype. Deletion of the second start codon and its downstream region inactivates the TK function. Those deletion mutants which contain only the third ATG codon are TK-. Thus, the 38-kDa polypeptide that initiates at the third start codon is not endowed with the TK+ activity. Constructs containing deletions up to nt +210 and lacking all 5'-end canonical and aberrant transcription control regions, as well as first start codon, can provide the TK+ function.
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PMID:Transient expression of deletion mutants of the herpes simplex virus thymidine kinase-encoding gene in mouse fibroblast cells. 165 25

The transcriptional induction of the alpha or immediate-early gene class of herpes simplex virus type 1 effected by the alpha trans-induction factor (alpha TIF, ICP25, VP16, Vmw65) requires an alpha-specific cis-acting site. Increased transcription does not result from the direct, independent binding of alpha TIF, but rather from an alpha TIF-dependent formation of a protein-DNA complex containing, in addition to alpha TIF, at least one host cell factor. One of the host factors is a POU domain protein which recognizes an octamer element in the alpha-specific consensus. There is evidence that alpha TIF may drive the formation of multiple protein-DNA complexes containing a POU protein and additional host factors. Previously, the gene products of UL46 and UL47 have been implicated in modulating the alpha TIF-dependent transcriptional induction of alpha genes. Our current studies have extended these analyses from a transient-expression system to a series of viral deletion mutants. In these studies we demonstrate that neither UL46- nor UL47-encoded gene product, either separately or in combination, is required for viral growth in cell culture. The absence of UL47 reduces by up to 80% the ability of the virus to induce an alpha-regulated thymidine kinase reporter gene resident in 143TK- cells. Autoradiograms of [35S]methionine pulse-labeled infected cell proteins, separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, show that deleting UL46 and/or UL47 has no discernable effect on the synthesis of alpha TIF or alpha TIF-containing proteins. Subsequent Western immunoblot analysis, with rabbit anti-alpha TIF antibodies made to an alpha TIF-Staphylococcus aureus protein A fusion, demonstrated that the accumulation and steady-state levels of alpha TIF or alpha TIF-containing proteins was indistinguishable from that of the thymidine kinase-negative isogenic parental virus, R delta 305.
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PMID:Role of herpes simplex virus type 1 UL46 and UL47 in alpha TIF-mediated transcriptional induction: characterization of three viral deletion mutants. 184 1


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