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At least 595 records · Page 33Linked to original sources
PubMed1998

Impaired differentiation of HPRT-deficient dopaminergic neurons: a possible mechanism underlying neuronal dysfunction in Lesch-Nyhan syndrome.

Lesch-Nyhan syndrome is a hereditary disorder of purine metabolism causing overproduction of uric acid and neurological problems including spasticity, choreoathetosis, mental retardation, and compulsive self-mutilation. The syndrome is caused by a defect in the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT), which converts guanine and hypoxanthine to the nucleotides GMP and IMP. There is evidence that the neurological problems are due to an adverse effect of the HPRT deficiency on the survival and/or development of dopaminergic neurons, specifically. Here we report that HPRT-deficient PC12 mutants that have a normal or near normal dopamine content (55-97% of that of wild-type cells) fail to undergo neuronal differentiation induced by nerve growth factor (NGF) when the de novo pathway of purine synthesis is partially inhibited. However, nerve growth factor-induced differentiation is near normal under these conditions in PC12 HPRT-deficient mutants containing much lower dopamine levels (<8% of that of wild type cells), indicating a neurotoxic effect of the endogenous dopamine in the mutants. The degree of inhibition of the de novo pathway of purine synthesis was the same in both classes of HPRT-deficient mutants. Expression of BCl-2 in a PC12 mutant that has a normal dopamine content allowed partial NGF-induced differentiation suggesting that the apoptotic pathway might be involved in the failure of differentiation when the de novo pathway of purine synthesis is partially inhibited.

Animals↗
PubMed1985

HGPRT- mutants of V79 cells that revert specifically by base pair substitution and frameshift mutations.

In order to determine the mutagenic specificity of mutagenic and carcinogenic agents in mammalian cells, a reversion system capable of distinguishing between frameshift mutations and various kinds of base pair substitutions would be useful. We report here a method for the isolation and characterization of HGPRT- Chinese hamster V79 cell mutants that might form the basis for such a system. Two mutants of different specificity have been partially characterized. DEW-1, isolated following N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) treatment, is revertible by the base pair substitution mutagens MNNG and ethyl methanesulfonate (EMS), but not by frameshift mutagens. DSW-3, isolated following ICR-191 treatment, is specifically reverted by frameshift mutagens, but not by EMS or MNNG. With the further characterization of these and other mutants, it should be feasible to determine not only whether an agent is mutagenic in V79 cells, but also to determine the type(s) of mutation(s) it produces.

Animals↗
PubMed1977

The inhibition by 6-diazo-5-oxo-l-norleucine of glutamine catabolism of the cultured human lymphoblast.

The rapid catabolism of glutamine by the cultured human lymphoblast line WI-L2 can be inhibited greater than 95% by incubation of cell suspensions with 6-diazo-5-oxo-L-norleucine (DON). The inhibition persists for at least four hours after removal of DON from the cell suspension. The exposure of cells to DON ihibits over 95% of the glutaminase activity measured in lysates in the presence of either phosphate or maleate. Similarly, gamma-glutamyl transpeptidase, assayed with gamma-glutamyl-p-nitroanilide as substrate and glycyglycine as acceptor, is inhibited over 90%. DON-treated and control cells accumulated radioactive material from suspensions containing [14C]-L-glutamine at similar initial rates; the radioactive material accumulated by the DON-treated cells is all recoverable as glutamine while the radioactive material accumulated by untreated cells is principally recovered as glutamate.

Azaserine↗