Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The acyclic nucleotide analogue (S)-9-(3-hydroxy-2-phosphonyl-methoxypropyl)-adenine [(S)-HPMPA], which contains a phosphonate-substituted aliphatic chain, is a potent and selective inhibitor of the replication of various DNA viruses, including herpes simplex virus type 1 (HSV-1). We have synthesized radiolabeled (S)-[U-14C-adenine]HPMPA and investigated its metabolism by HSV-1-infected and mock-infected cells. The drug is as such taken up by the cells and subsequently converted to its monophosphoryl [(S)-HPMPAp] and diphosphoryl [(S)-HPMPApp] derivatives by cellular enzymes. It is incorporated to a very low extent into DNA of both mock-infected and HSV-1-infected Vero cells. (S)-HPMPA inhibits HSV-1 DNA synthesis at a concentration that is several orders of magnitude lower than the concentration required for inhibition of cellular DNA synthesis. Thus the selectivity of (S)-HPMPA as an antiviral agent cannot be attributed to a differential phosphorylation by virus-infected or uninfected cells but resides in a specific inhibitory effect on viral DNA synthesis. The exact basis for the latter effect is under investigation.
Mol Pharmacol 1987 Oct
PMID:Intracellular phosphorylation of broad-spectrum anti-DNA virus agent (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine and inhibition of viral DNA synthesis. 282 95

Cleavage and polyadenylation of substrate RNAs containing the herpes simplex virus type 1 (HSV-1) thymidine kinase (tk) gene polyadenylation signal region were examined in HeLa cell nuclear extract. 3'-End RNA processing was accurate and efficient and required ATP and Mg2+. Cleavage, but not polyadenylation, occurred in the presence of EDTA or when ATP was replaced with 3' dATP (cordycepin) or AMP(CH2)PP, a nonhydrolyzable analog of ATP. Processing in vitro and in vivo showed the same signal element requirements: a series of substrates containing linker scanning, internal deletion, and small insertion mutations was processed with the same relative efficiencies and at the same sites in vitro and in vivo. A complex involved in 3'-end RNA processing was identified by gel mobility shift analysis. This complex formed rapidly, reached a maximum level after 20 to 30 min, and was much reduced after 2 h. Very little complex was formed at 0 degree C or with substrates lacking a polyadenylation signal. Entry of 32P-labeled tk substrate into the complex could be prevented by addition of excess 35S-labeled tk or adenovirus L3 precursor RNAs. Competition was not observed with tk RNAs lacking a complete polyadenylation signal.
Mol Cell Biol 1987 Sep
PMID:Identification of a complex associated with processing and polyadenylation in vitro of herpes simplex virus type 1 thymidine kinase precursor RNA. 282 24

The virtually complete deficiency of the purine salvage enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT) results in a devastating neurological disease, Lesch-Nyhan syndrome. Transfer of the HPRT gene into fibroblasts and lymphoblasts in vitro and into hematopoietic cells in vivo has been accomplished by other groups with retroviral-derived vectors. It appears to be necessary, however, to transfer the HPRT gene into neuronal cells to correct the neurological dysfunction of this disorder. The neurotropic virus herpes simplex virus type 1 has features that make it suitable for use as a vector to transfer the HPRT gene into neuronal tissue. This report describes the isolation of an HPRT-deficient rat neuroma cell line, designated B103-4C, and the construction of a recombinant herpes simplex virus type 1 that contained human HPRT cDNA. These recombinant viruses were used to infect B103-4C cells. Infected cells expressed HPRT activity which was human in origin.
Mol Cell Biol 1988 Jan
PMID:Herpes simplex virus-mediated human hypoxanthine-guanine phosphoribosyltransferase gene transfer into neuronal cells. 282 6

The effect of nucleoside-5-triphosphates analogues on the DNA polymerase of herpes simplex virus (HSV) has been investigated. Evidence is obtained that 3-amino-2,3-dideoxythymidine triphosphate selectively inhibits the DNA synthesis, catalyzed by HSV DNA polymerase. 3-amino-2,3-dideoxythymidine exhibits antiherpetic effect in single cells cultures. It may be phosphorylated by cellular thymidine kinase. The nuclei of Vero cells infected by HSV are an adequate system for antiherpetic compounds screening.
Mol Gen Mikrobiol Virusol 1987 Oct
PMID:[Inhibitory effect of various analogs of nucleoside-5'-triphosphates on DNA synthesis catalyzed by DNA polymerase from herpes simplex virus type I]. 282 34

A 2 micron circle-based chimaeric plasmid containing the yeast LEU2 and the Herpes Simplex Virus type 1 thymidine kinase (HSV-1 TK) genes was constructed. Transformants grown under selective conditions for the LEU2 gene harboured the plasmid at about 15 copies per cell whilst selection for the HSV-1 TK gene led to an increase to about 100 copies per cell. Furthermore, the plasmid copy number could be controlled by the stringency of selection for the TK gene, and the increase in TK gene dosage was reflected in an increase in intracellular thymidine kinase activity. The mitotic stability of the plasmid in "high-copy" and "low-copy" number cells was determined. "High-copy" number cells showed a greater mitotic stability. The relationship of TK expression to plasmid copy number may be useful for the isolation of plasmid copy number mutants in yeast and the control of heterologous gene expression.
Mol Gen Genet 1988 Jan
PMID:Amplification of plasmid copy number by thymidine kinase expression in Saccharomyces cerevisiae. 283 Apr 62

The interferon (IFN)-activated human 2',5'-oligo(A) synthetase E gene contains 11 RNA starts and lacks TATA and CAAT signals. DNA sequences around the promoter make the expression of the chloramphenicol acetyltransferase gene (CAT) inducible over 20-fold by IFN. A 72-base-pair segment (E-IRS) immediately upstream of the RNA starts was defined as being required for IFN-activated expression of the E-gene promoter-CAT constructs and acts in a position-independent manner. It also confers IFN-activated enhancement to the herpes simplex virus thymidine kinase promoter. On this promoter, the 5' part of the E-IRS functions as a constitutive enhancer, while the last 16 base pairs of the E-IRS is sufficient to give IFN-induced expression. On the E-gene promoter, the constitutive enhancer and the IFN-activated sequence are both needed but can be separated. In addition, promoter competition experiments indicate a third regulatory region which helps to repress expression of the E gene in uninduced cells.
Mol Cell Biol 1987 Dec
PMID:Interferon-responsive regulatory elements in the promoter of the human 2',5'-oligo(A) synthetase gene. 283 Apr 97

To study the influence of clustered highly repetitive DNA sequences on the expression of adjacent genes, LTK- cells were cotransfected with the herpes simplex virus thymidine kinase (tk) gene and mouse satellite DNA. TK+ transformants containing a few copies of the tk genes flanked by satellite DNA were isolated. In situ hybridization on the metaphase chromosomes indicated that in each cell line the TK sequences resided at a single chromosomal site and that integration occurred preferentially into regions of the cellular DNA rich in highly repetitive sequences. The prominent feature of these cell lines was their phenotypic instability. Suppression and reexpression of the tk gene occurred at high frequency (greater than 3%) and did not correlate with any significant change in the organization of foreign DNA or with the presence of selective agents. These results indicate that satellite DNA, the major component of constitutive heterochromatin, may influence the expression of adjacent genes by affecting the chromatin structure.
Mol Cell Biol 1988 Mar
PMID:Satellite DNA induces unstable expression of the adjacent herpes simplex virus tk gene cotransfected in mouse cells. 283 71

Infection of rat embryo cells with herpes simplex virus type 2 caused undermethylation of host cell DNA synthesized during infection. DNA made prior to infection was not demethylated, but some of its degradation products, including methyl dCMP, were incorporated into viral DNA. The use of mutant virus showed that some viral DNA synthesis appears to be required for the inhibition of methylation. Inhibition of methylation cannot be explained by an absence of DNA methyltransferase as the activity of this enzyme did not change during the early period of infection. Inhibition of host cell DNA methylation may be an important step in the transformation of cells by herpesviruses, and various transformed cell lines tested showed reduced levels of DNA methylation.
Mol Cell Biol 1988 Apr
PMID:Hypomethylation of host cell DNA synthesized after infection or transformation of cells by herpes simplex virus. 283 42

The distribution of capsid proteins induced by herpes simplex virus type 1 infection was determined at the ultrastructural level. The antiserum A to total capsid proteins and the anti-NC1 and NC2 sera, all labeled with gold particles, decorated the entire thickness of both empty capsids and nucleocapsids filled with viral DNA. On the other hand, an antibody to NC3,4 protein produced a heavy labeling concentrated almost entirely along the internal surface of empty capsids, whereas full capsids were not labeled. DNase digestion of "full" capsids did not restore anti-NC3,4 protein binding at this site. Published biochemical data concerning viral protein distribution in capsids are conflicting, but if NC3,4 protein is present in full capsids, we suggest that new binding forces between capsid proteins occurred at the time of insertion of viral DNA which might conceal the relevant antigenic sites of NC3,4 proteins. Capsid proteins were abundantly present in the viral nucleoplasm and in most constituents of the infected cells particularly some nucleoli and some but not all dense bodies. However, whereas anti-NC1 serum labeled nucleoli but not dense bodies, both anti-NC2 and anti-NC3,4 sera stained only dense bodies but not nucleoli. Inhibition of replication of viral DNA which entered the cell during the infective period did not inhibit the production of capsid proteins. Inhibition of protein synthesis in late infected cells did not alter the distribution of capsid proteins.
J Ultrastruct Mol Struct Res 1988 Mar
PMID:Involvement of nucleoli and dense bodies in the intranuclear distribution of some capsid polypeptides in cells infected with herpes simplex virus type 1. 284 85

Enhanced reactivation of Ultraviolet-irradiated virus has been reported to occur in heat-shocked host cells. Since enhanced virus reactivation is often accompanied by untargeted mutagenesis, we investigated whether such mutagenesis would occur for herpes simplex virus (HSV) in CV-1 monkey kidney cells subjected to heat shock. In addition to expressing enhanced reactivation, the treated cells were transiently more susceptible to infection by unirradiated HSV. No mutagenesis of unirradiated HSV was found whether infection occurred at the time of increased susceptibility to infection or during expression of enhanced viral reactivation.
Environ Mol Mutagen 1988
PMID:Heat shock and herpes virus: enhanced reactivation without untargeted mutagenesis. 284 52


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