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Query: UNIPROT:P06889 (Mol)
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Plasmids containing the hormone regulatory element of mouse mammary tumor virus linked to the thymidine kinase promoter of herpes simplex virus and the reporter gene chloramphenicol acetyltransferase of Escherichia coli respond to glucocorticoids and progestins when transfected into appropriate cells. In the human mammary tumor cell line T47D, the response to progestins, but not to glucocorticoids, is highly dependent on the topology of the transfected DNA. Although negatively supercoiled plasmids respond optimally to the synthetic progestin R5020, their linearized counterparts exhibit markedly reduced progestin inducibility. This is not due to changes in the efficiency of DNA transfection, since the amount of DNA incorporated into the cell nucleus is not significantly dependent on the initial topology of the plasmids. In contrast, cotransfection experiments with glucocorticoid receptor cDNA in the same cell line show no significant influence of DNA topology on induction by dexamethasone. A similar result was obtained with fibroblasts that contain endogenous glucocorticoid receptors. When the distance between receptor-binding sites or between the binding sites and the promoter was increased, the dependence of progestin induction on DNA topology was more pronounced. In contrast to the original plasmid, these constructs also revealed a similar topological dependence for induction by glucocorticoids. The differential influence of DNA topology is not due to differences in the affinity of the two hormone receptors for DNA of various topologies, but probably reflects an influence of DNA topology on the interaction between different DNA-bound receptor molecules and between receptors and other transcription factors.
Mol Cell Biol 1990 Feb
PMID:Hormonal induction of transfected genes depends on DNA topology. 215 20

The carbocyclic analogue of (E)-5-(2-iodovinyl)-2'-deoxyuridine (C-IVDU) is, like its parent compound (E)-5-(2-iodovinyl)-2'-deoxyuridine (IVDU), a potent and selective inhibitor of herpes simplex virus type 1 (HSV-1). There is a close correlation between the inhibition of viral DNA synthesis and the antiviral activity of both IVDU and C-IVDU. IVDU and C-IVDU inhibit viral DNA synthesis at 0.2 and 0.5 microM, respectively, and interfere with cellular DNA synthesis at concentrations that are 10- to 40-fold in excess of their antivirally effective doses. At concentrations affording a similar antiviral effect, C-[125I]IVDU is incorporated into viral and cellular DNA of HSV-1-infected Vero cells to a 7- to 10-fold lesser extent than IVDU. [125I]IVDU but not C-[125I]IVDU leads to breakage of both DNA strands when incorporated into HSV-1 DNA.
Mol Pharmacol 1990 Mar
PMID:Role of the incorporation of (E)-5-(2-iodovinyl)-2'-deoxyuridine and its carbocyclic analogue into DNA of herpes simplex virus type 1-infected cells in the antiviral effects of these compounds. 215 54

The (+)- and (-)-enantiomers of the carbocyclic analogues of (E)-5-(2-bromovinyl)-2'-deoxyuridine (C-BVDU) and 5-iodo-2'-deoxyuridine (C-IDU) were synthesized by separate routes. Both the (+)- and (-)-enantiomers of C-BVDU and C-IDU were markedly inhibitory to herpes simplex virus type 1 (HSV-1) replication. (+)-C-BVDU and (+)-C-IDU were as inhibitory to HSV-1 as the racemic (+/-)-C-BVDU and (+/-)-C-IDU, respectively, whereas the (-)-enantiomers were only 10-fold less active. Also, the (+)- and (-)-enantiomers of C-BVDU were equally inhibitory to the growth of murine mammary carcinoma cells transformed by the HSV-1 or HSV-2 thymidine kinase (TK) gene (designated FM3A TK-/HSV-1 TK+ and FM3A TK-/HSV-2 TK+). The (+)- and (-)-enantiomers of C-BVDU and the (+)- and (-)-enantiomers of C-IDU had a remarkably similar affinity for HSV-1 TK [Ki, 0.09 and 0.19 microM for (+)-C-BVDU and (+)-C-IDU and 0.16 and 0.19 microM for (-)-C-BVDU and (-)-C-IDU, respectively]. The inhibition of HSV-1 TK by BVDU, IDU, (+)-C-BVDU, and (+)-C-IDU was purely competitive with regard to the natural substrate (thymidine), whereas (-)-C-BVDU, (-)-C-IDU, (+/-)-C-BVDU, and (+/-)C-IDU showed a linear mixed-type inhibition of HSV-1 TK. C-BVDU and C-IDU are examples of chiral molecules of which both isomeric forms are markedly active at both the cellular and enzymatic level.
Mol Pharmacol 1990 Mar
PMID:Carbocyclic 5-iodo-2'-deoxyuridine (C-IDU) and carbocyclic (E)-5-(2-bromovinyl)-2'-deoxyuridine (C-BVDU) as unique examples of chiral molecules where the two enantiomeric forms are biologically active: interaction of the (+)- and (-)-enantiomers of C-IDU and C-BVDU with the thymidine kinase of herpes simplex virus type 1. 215 53

We have two goals in this review: the first is to relate what has been learned about DNA replication from the study primarily of herpes simplex virus type 1 (HSV-1); the second is to note briefly facets of this virus's mode of DNA replication that might serve as points of intervention for novel chemotherapeutic approaches in order to deal with primary and recurrent herpesvirus infections in man and animals. For the first goal we shall both summarize what has been learned and attempt to identify directions that may be pursued in order to further our understanding of DNA replication by herpesviruses. For the second goal we shall propose two schemes for the screening for drugs that might interfere uniquely with the DNA replication of this family of viruses.
Mol Biol Med 1990 Feb
PMID:DNA replication of herpesviruses during the lytic phase of their life-cycles. 215 36

Modifications of ribosomes have been investigated in human epidermoid carcinoma-2 cells at different stages of herpes simplex virus type 1 infection. Very early in infection, there is an increase in ribosomal protein S6 phosphorylation even in the absence of serum. The same result is obtained in the presence of actinomycin D. At early infection time, ribosomal proteins S2, S3a and Sa are newly phosphorylated. At early and early-late times, three phosphorylated non-ribosomal proteins (v1, v2 and v3) are differently associated temporally to ribosomes. Analyses of proteins extracted from 40S subunits, 80S ribosomes and polysomes show that v1 and v2 are distributed differently among the different ribosomal populations. S6 phosphopeptides were found to be identical after serum stimulation and after viral infection. In every case phosphoserine and phosphothreonine were identified in S6. Only phosphoserine was found in other phosphorylated proteins. Our results indicate that herpes simplex virus type 1 is able to modify pre-existing ribosomes: (i) by stimulating a pre-existing kinase for S6 phosphorylation even in the absence of serum and of viral genome expression; (ii) by inducing new specific kinase activity(ies); and (iii) by association of new, phosphorylated proteins to ribosomes. These ribosomal modifications are correlated with changes in protein synthesis, as shown by two-dimensional electrophoretic analyses of newly synthesized 35S-labelled proteins.
Mol Gen Genet 1990 Feb
PMID:Ribosome and protein synthesis modifications after infection of human epidermoid carcinoma cells with herpes simplex virus type 1. 216 50

5-(2-Chloroethyl)-2'-deoxyuridine (CEDU) is a potent and selective inhibitor of the replication of herpes simplex virus type 1 (HSV-1). CEDU is preferentially phosphorylated by HSV-infected (Vero) cells, as compared with mock-infected cells or cells infected with a thymidine kinase-deficient strain of HSV-1. The end product of this phosphorylation process, CEDU 5'-triphosphate, is a competitive inhibitor of HSV-1 DNA polymerase activity and, to a lesser extent, of cellular DNA polymerase alpha activity. However, in the absence of the natural substrate dTTP, CEDU 5'-triphosphate also serves as an alternative substrate for viral and cellular DNA polymerase. When exposed to HSV-1-infected cells, [2-14C]CEDU was incorporated into both viral and cellular DNA. The extent to which [2-14C]CEDU was incorporated remained approximately constant over a concentration range of 0.5 to 50 microM. Within this concentration range, CEDU effected a concentration-dependent inhibition of viral DNA synthesis that closely paralleled the inhibition of viral progeny formation. It is postulated that CEDU owes (i) its selectivity as an antiviral agent to its preferential phosphorylation by the virus-infected cell and (ii) its antiviral potency to an inhibition of viral DNA synthesis at the level of the viral DNA polymerization reaction.
Mol Pharmacol 1990 May
PMID:Mechanism of action of 5-(2-chloroethyl)-2'-deoxyuridine, a selective inhibitor of herpes simplex virus replication. 216 59

The effects of herpes simplex virus type 1 (HSV-1) infection on proteoglycan synthesis by human endothelial cells were studied as a model of endothelial cell injury. Confluent cultures of early passage endothelial cells from human umbilical vein were infected with HSV-1 at multiplicities of infection from 0.001 to 1.0. HSV-1 infection produced a dose-dependent inhibition of total proteoglycan synthesis of up to 85%. Although there was a 2- to 3-fold increase in the quantity of virus necessary to cause 50% inhibition of heparan sulfate compared to chondroitin/dermatan sulfate proteoglycan, the inhibition was relatively parallel, even up to high virus doses. There was no inhibition of an undersulfated heparan sulfate proteoglycan that contained glycosaminoglycan chains shorter than the predominant species. The results indicate that HSV-1 infection of human endothelial cells produces complex effects on host-cell metabolism. The viral-induced changes in proteoglycan metabolism may influence cell-matrix interactions and lead to altered vessel wall function.
Am J Respir Cell Mol Biol 1990 May
PMID:Inhibition of proteoglycan synthesis in human endothelial cells after infection with herpes simplex virus type 1 in vitro. 216 Feb 54

The herpes simplex virus virion protein Vmw65 trans activates the viral immediate-early genes and some octamer-containing cellular genes, including that encoding histone H2B. We found, however, that a truncated form of this virion protein repressed H2B gene transcription and also dominantly inhibited induction of the gene by intact Vmw65. A cell line expressing this truncated protein expressed reduced levels of H2B and grew more slowly than the parental cell line or a similar line expressing the intact protein.
Mol Cell Biol 1990 Jun
PMID:Inhibition of histone H2B gene transcription and of cellular growth by a truncated viral trans-activator protein. 216 May 97

A novel mammalian regulatory system was created by using the Escherichia coli lac repressor. The lac repressor was converted into a mammalian transcriptional activator by modifying the lac repressor coding region to include a nuclear localization signal from the simian virus 40 (SV40) large tumor antigen and the transcription activation domain from the herpes simplex virus type 1 virion protein 16. The lac activator protein (LAP) fusions were potent activators of several promoters containing lac operator sequences positioned either upstream or downstream of the transcription unit. A single lac operator allowed for transactivation, whereas multiple operators acted synergistically when separated by a small distance. Promoters containing 14 or 21 operator sequences were induced at least 1,000-fold in response to LAP, reaching levels of activity 20 to 30 times greater than that of the SV40 early promoter in HeLa cells. Activation was strongly inhibited by isopropyl-beta-D-thiogalactoside (IPTG), indicating that LAP retained the functions needed for allosteric regulation. LAP was bifunctional, also acting as a repressor of expression of an SV40 promoter containing an operator immediately downstream of the TATA box. Finally, genetic selection schemes were developed such that LAP-expressing cell lines can be generated at high frequency from either established or primary cells in culture.
Mol Cell Biol 1990 Jul
PMID:Conversion of the lac repressor into an allosterically regulated transcriptional activator for mammalian cells. 216 73

The influence of different CC Ar GG boxes derived from either muscle-specific or serum-responsive genes, on the specificity of different promoters has been investigated. Inserted upstream from an 85 base-pair long minimal promoter of the human cardiac alpha-actin gene, a single copy of both the cognate CC Ar GG element (HCA1) and the c-fos gene serum response element (SRE) stimulate transcription four- to fivefold more efficiently in C2 myogenic cells than in L fibroblastic cells, SRE being two- to threefold more active than HCA1. Inserted upstream from the ubiquitous Herpes simplex thymidine kinase (HSV-tk) promoter, multimerized CC Ar GG boxes behave as strong muscle-specific activating elements, about 20-fold more active in myogenic C2 cells than in L fibroblasts and hepatoma HepG2 cells. They also confer serum responsiveness on the HSV-tk promoter. Efficiency of HCA1 and SRE tetramers in conferring both muscle specificity and serum responsiveness is roughly similar. It appears, therefore, that regardless of their origin (either muscle-specific or serum-responsive genes) CC Ar GG boxes behave by themselves as both muscle-specific activating and serum-responsive elements.
J Mol Biol 1990 Jun 20
PMID:CC Ar GG boxes, cis-acting elements with a dual specificity. Muscle-specific transcriptional activation and serum responsiveness. 216 66


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