Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.1.21 (thymidine kinase)
 7,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dideoxynucleotide sequence analysis of a spontaneously isolated deletion variant (1714) of Glasgow strain 17+ of herpes simplex virus type 1 (HSV-1) demonstrates that the deletion is 759 bp in length and is located within each copy of the BamHI s fragment (0 to 0.02 and 0.81 to 0.83 map units) of the long repeat region of the genome. The deletion removes one complete copy of the 18 bp DR1 element of the 'a' sequence and terminates 1105 bp upstream of the 5' end of immediate early (IE) gene 1. The variant grows to high titre, is not temperature-sensitive and is not host cell type-restricted in vitro. In vivo studies demonstrate that 1714 is totally avirulent for BALB/c mice following intracerebral inoculation, with an LD50 of 7 x 10(6) p.f.u./mouse compared to less than 10 p.f.u./mouse for the parental wild-type strain 17+. In vivo growth kinetics show that the non-neurovirulent phenotype is due to an inability to replicate in mouse brain. Because 1714 was in a genomic background in which the four XbaI sites had been removed and because the phenotype was thymidine kinase-negative, the 759 bp deletion was introduced into an otherwise totally wild-type background. The resulting variant (1716) is non-neurovirulent for mice, with an LD50 of 7 x 10(6) p.f.u./mouse. The deletion does not prevent the virus from establishing a latent infection or reactivating from it in vitro. The results demonstrate that sequences between IE-1 and the 'a' sequence produce neurovirulence in Glasgow strain 17+ and, in conjunction with the non-neurovirulence of the HSV-2 HG52 variant JH2604, identify a common function conserved in HSV-1 and -2.
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PMID:Herpes simplex virus type 1 deletion variants 1714 and 1716 pinpoint neurovirulence-related sequences in Glasgow strain 17+ between immediate early gene 1 and the 'a' sequence. 184 98

Previous studies have shown that the a sequence located at the termini and at the junction between the L and S components is the site-specific, cis-acting sequence mediating the inversions of herpes simplex virus 1 DNA. We constructed mutated a sequences, inserted them into the thymidine kinase gene, and recombined them into the L component of the viral genome. Deletion of Uc or Ub domains of the a sequence did not affect inversions, whereas the deletion of direct repeat #4 (DR4) drastically reduced their frequency. Deletion of both direct repeat #2 (DR2) and DR4 abolished inversions. Recombinational events leading to inversions appear to occur through DR2, and possibly DR4. These results complement previous studies showing that most of one DR1 sequence can also be dispensed with and are consistent with the hypothesis that DR4 and possibly DR2 are the cis-acting sites for the inversions mediated by the a sequence.
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PMID:Isomerization of herpes simplex virus 1 genome: identification of the cis-acting and recombination sites within the domain of the a sequence. 298 89

Retinoic acid (RA) is known to have potent effects on development and differentiation. RA exerts its effects on transcription through two distinct classes of nuclear receptors, the retinoic acid receptor (RAR) and the retinoid X receptor (RXR), that bind to specific RA-responsive elements (RARE) in target genes. alpha-Fetoprotein (AFP), a hepatocyte differentiation, maturation, and carcinogenesis marker, is transcriptionally upregulated by RA in McA-RH8994 hepatoma cells. Using deletion mapping analysis, we have identified a RARE-like sequence that is located between -2406 and -2378 of the transcription initiation site of the rat AFP gene. Sequence analysis demonstrated that this cis-acting element consists of three direct repeats and one inverted repeat of a GGGTCA-like half-site. The putative RARE can specifically bind to both RXR homodimers and RAR/RXR heterodimers as determined by gel mobility shift assays. A DR1 direct repeat was more efficient than a DR5 direct repeat oligonucleotide in competition for binding of the putative RARE to RXR and RAR/RXR. A mutagenesis study indicated that to have a full-strength induction, all the repeats were required. To further analyze the function of this element in vivo, a reporter gene construct of the putative RARE combined with the thymidine kinase promoter was cotransfected with RAR and RXR expression plasmids in CV1 cells. CAT assays demonstrated that overexpression of RXRalpha conferred the best RA response, consistent with our previous observation that 9-cis-RA is more potent than all-trans-RA for inducing the expression of the AFP gene. In addition, the RXR selective ligand LG100153 alone can stimulate the expression of the AFP gene. Our data suggest that an RXR-mediated pathway exists for modulation of AFP gene expression through a specific element.
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PMID:RXR-mediated regulation of the alpha-fetoprotein gene through an upstream element. 894 36