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

Syndecan-1 (SDC1), a transmembrane heparan sulfate proteoglycan that participates in the binding and internalization of extracellular ligands, was identified in a screen designed to isolate genes that are regulated by the farnesoid X-receptor (FXR, NR1H4). Treatment of human hepatocytes with either naturally occurring (chenodeoxycholic acid) or synthetic (GW4064) FXR ligands resulted in both induction of SDC1 mRNA and enhanced binding, internalization, and degradation of low density lipoprotein. Transient transfection assays, using wild-type and mutant SDC1 promoter-luciferase genes, led to the identification of a nuclear hormone receptor-binding hexad arranged as a direct repeat separated by one nucleotide (DR-1) in the proximal promoter that was necessary and sufficient for activation by FXR. The wild-type, but not a mutated DR-1 element, conferred FXR responsiveness to a heterologous thymidine kinase promoter-reporter gene. Four murine FXR isoforms have been identified recently that differ either at their amino terminus and/or by the presence or absence of four amino acids in the hinge region. Interestingly, the activities of the human SDC1 promoter-reporter constructs were highly induced by the two FXR isoforms that do not contain the four-amino acid insert and were unresponsive to the isoforms containing the four amino acids. Thus, current studies demonstrate that hepatic SDC1 is induced in an FXR isoform-specific manner. Increased expression of SDC1 may account in part for the hypotriglyceridemic effect that can result from the administration of chenodeoxycholic acid to humans.
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PMID:Syndecan-1 expression is regulated in an isoform-specific manner by the farnesoid-X receptor. 1266 Feb 31

The ubiquitous expression of cell surface heparan sulfate proteoglycan, a binding receptor for adeno-associated virus type 2 (AAV-2), may account for the broad host range of this vector. Because the fibroblast growth factor receptor type 1 has been postulated to be a coreceptor for successful AAV-2 entry into host cells, we designed a strategy to investigate whether coadministration of this virus with basic fibroblast growth factor (bFGF) can enhance AAV-2-mediated gene delivery. We injected AAV-2-thymidine kinase (AAV-2-TK) vector into rat striata and checked whether coinjection with bFGF enhanced transduction and/or enlarged the area of transgene expression. Immunostaining confirmed the tropism of AAV-2-TK for neurons. The previous injection (7 days before vector delivery) of bFGF had no major impact on vector distribution area. However, when the vector was coinjected with bFGF, the right striatum showed an average viral transduction volume of 5 mm(3), which was more than 4-fold larger when compared with the left side (AAV-2-TK plus phosphate-buffered saline). This result clearly indicates that simultaneous injection of bFGF with AAV-2-TK can greatly enhance the volume of transduced tissue, probably by way of a competitive block of AAV-2-binding sites within the striatum. Robust TK immunoreactivity was also observed in the globus pallidus, which receives anterograde projections from the striatum. We propose that postsynaptic transport of recombinant particles was likely responsible for the distribution of TK in the globus pallidus on both bFGF-treated and untreated sides. In summary, we found that bFGF acts as an adjuvant for distribution of AAV-2 in rat brain.
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PMID:Basic fibroblast growth factor enhances transduction, distribution, and axonal transport of adeno-associated virus type 2 vector in rat brain. 1514 77

Cancer suicide gene therapy based on herpes simplex virus type I thymidine kinase (HSV-TK) and ganciclovir (GCV) suffers from the lack of efficacy in clinical use, which is mostly due to low gene-transfer efficiency and absence of bystander effect in tumors. We have previously demonstrated the enhancement of GCV cytotoxicity by fusing the HSV-TK with the cell penetrating peptide from HIV-1 transactivator protein transduction domain (TAT PTD). Despite the earlier promising results, we found that the triple fusion protein HIV-1 transactivator protein transduction domain-thymidine kinase suicide gene-green fluorescent protein marker gene (TAT-TK-GFP) increased GCV cytotoxicity only in 3/12 of different human tumor cell lines. Extended GCV exposure enhanced the cytotoxic effect of HSV-TK/GCV gene therapy, but the difference between TK-GFP and TAT-TK-GFP was not statistically significant. The modest improvement on cell killing mediated by TAT PTD in Chinese hamster ovary cells appeared to be associated with cell-surface heparan sulfate proteoglycan (HSPG) composition. However, TAT-mediated increased cell death did not correlate with the density of cell-surface HSPG expression in different tumor cell lines. In conclusion, although some degree of enhancement by TAT was shown in certain tumor cells in vitro, it is unlikely that TAT peptide linked to a suicide protein could be a useful booster of in vivo gene therapy trials.
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PMID:Characterization of HIV-1 TAT peptide as an enhancer of HSV-TK/GCV cancer gene therapy. 1830 53