Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.4.2.8 (hypoxanthine-guanine phosphoribosyltransferase)
 2,527 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

BALB/c mouse thymoma-derived T cell line, CAK4.4 (Thy-1+, L3T4-, Lyt-2-), produced a large amount of TCR-gamma mRNA, a trace amount of TCR-beta mRNA but no detectable level of TCR-alpha mRNA. Another BALB/c mouse thymoma-derived T cell line, CAK1.3 (Thy-1+, L3T4+, Lyt-2+), synthesized a high level of TCR-alpha as well as TCR-beta mRNA but did not produce any amount of TCR-gamma mRNA. HAT-sensitive clones were established from the two T cell lines. Azaguanine-resistant, HPRT- CAK4.4 cells and bromodeoxyuridine-resistant, TK- CAK1.3 cells were fused by electrofusion method and the resultant hybrids were analyzed for expression of TCR genes as well as the changes of their cell surface phenotypes. Transcription of TCR-gamma gene was completely suppressed in all hybrids tested, although Southern blot analysis showed that the hybrids maintained TCR-gamma chain genes derived from both parental cells. TCR-alpha gene transcription occurred normally in one hybrid. In two other hybrids, TCR-alpha gene transcription was strongly suppressed. Treatment of the hybrid cells with 12-O-tetradecanoyl phorbol-13-acetate reversed the suppression of TCR-alpha gene transcription, but TCR-gamma gene transcription was not recovered by the same treatment. However, transcription level of TCR-beta gene was not changed in all hybrids. Our results suggested that the different trans-acting regulatory mechanisms control the transcription levels of TCR-alpha and TCR-gamma genes and that such a transcriptional control may play a crucial role in the determination of orderly appearance of TCR-gamma and TCR-alpha gene products during T cell ontogeny in the thymus.
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PMID:Trans-acting regulatory factors for T cell antigen receptor alpha- and gamma-chain gene expression. 283 44

The study deals with intragenic complementation between clones of Chinese hamster cells carrying mutations in the HPRT gene. All clones were of independent origin, selected in media containing one of three purine bases: 8-azaguanine (8 AG), 6-mercaptopurine (6MP), or 6-thioguanine (6TG). Some of the clones were spontaneous, others were induced by various mutagens. To make the study less time-consuming, an experimental set-up was proposed for simultaneous complementation testing of up to 10 clones. As a result, about 400 combinations of clones have been analyzed. Twelve pairs of complementating mutants have been identified in HAT medium. A linear complementation map has been constructed for the HPRT locus, showing five complementation groups. The changes in kinetic and other characteristics observed for mutant HPRT show that all the mutants studied carry structural gene mutations. Analysis of the biochemical characteristics of HPRT has revealed considerable differences between mutant enzymes in clones belonging to different complementation groups (three groups were examined). At the same time, the four mutant clones of complementation group II show similar HPRT characteristics, suggesting a relative similarity of their structural variants of the enzyme. The hybrid nature of HPRT in clones resulting from the fusion of mutant cells confirms the intragenic nature of complementation.
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PMID:Complementation analysis of locus for hypoxanthine guanine phosphoribosyltransferase in Chinese hamster cells. 385 54

6-Mercaptopurine and 6-thioguanine strongly inhibited the zero-trans entry of hypoxanthine into Novikoff rat hepatoma cells which lacked hypoxanthine/guanine phosphoribosyltransferase, whereas 8-azaguanine had no significant effect. 6-Mercaptopurine was transported by the hypoxanthine carrier with about the same efficiency as its natural substrates (Michaelis-Menten constant = 372 +/- 23 microM; maximum velocity = 30 +/- 0.7 pmol/microl cell H2O per s). 8-Azaguanine entry into the cells, on the other hand, showed no sign of saturability and was not significantly affected by substrates of the hypoxanthine/guanine carrier. The rate of entry of 8-azaguanine at 10-100 microM amounted to only about 5% of that of hypoxanthine transport and was related to its lipid solubility in the same manner as observed for various substances whose permeation through the plasma membrane is believed to be non-mediated. Only the non-ionized form of 8-azaguanine (pKa = 6.6) permeated the cell membrane. Studies with wild type Novikoff cells showed that permeation into the cell was the main rate-determining step in the conversion of extracellular 8-azaguanine to intracellular aza-GTP and its incorporation into nucleic acids. In contrast, 6-mercaptopurine was rapidly transported into cells and phosphoribosylated; the main rate-determining step in its incorporation into nucleic acids was the further conversion of 6-mercaptopurine riboside 5'-monophosphate.
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PMID:Facilitated transport of 6-mercaptopurine and 6-thioguanine and non-mediated permeation of 8-azaguanine in Novikoff rat hepatoma cells and relationship to intracellular phosphoribosylation. 719 51

The role of guanine deaminase in selective cellular resistance to 8-azaguanine was examined, using eight mammalian cell lines and their subclonal derivatives isolated on the basis of increasing resistance to this drug. 8-Azaguanine and 6-thioguanine are synthetic analogs of guanine and are lethal to cells with normal hypoxanthine phosphoribosyltransferase (HPRT) activity. In principle, however, HPRT-positive cells could become selectively resistant to 8-azaguanine if, by any mechanism, the cells expressed higher levels of guanine deaminase. This is because 8-azaguanine, but not 6-thioguanine, is converted by this enzyme to a noncytotoxic metabolite, 8-azaxanthine. Our study shows that HPRT-positive cells inherently resistant to relatively high levels of 8-azaguanine contain high levels of guanine deaminase. In general, guanine deaminase activity was higher in 8-azaguanine-resistant cells, regardless of their HPRT activity. Our results support the view that elevated guanine deaminase activity constitutes a potential mechanism of selective 8-azaguanine resistance in cells with normal HPRT activity. Guanine deaminase levels were significantly elevated in HPRT-positive cells briefly exposed to sublethal concentrations of 8-azaguanine, but this elevation was transient. Long-term exposure of cells to increasingly higher levels of the drug did not lead to high stable levels of guanine deaminase, indicating that 8-azaguanine is not an inducer of guanine deaminase in the cells examined.
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PMID:Specific resistance to 8-azaguanine in cells with normal hypoxanthine phosphoribosyltransferase (HPRT) activity: the role of guanine deaminase. 727 56