Posttranscriptionally mediated decreases in folylpolyglutamate synthetase gene expression in some folate analogue-resistant variants of the L1210 cell. Evidence for an altered cognate mRNA in the variants affecting the rate of de novo synthesis of the enzyme.

L1210 cell variants resistant to edatrexate (EDX) were isolated by selection in vivo during therapy with this folate analogue. Among the variants selected, seven (L1210/EDX-4 to -7 and L1210/EDX-12 to -14) were found to exhibit 2-23-fold lower levels of folylpolyglutamate synthetase (FPGS) activity compared with parental L1210 cells. Lower levels of FPGS activity in cell-free extract from these variants using EDX as substrate were characterized by the same relative decrease in value for Vmax with no change in apparent Km.

Different antifolate-resistant L1210 cell variants with either increased or decreased folylpolyglutamate synthetase gene expression at the level of mRNA transcription.

L1210 cell variants selected in the presence of the lipophilic dihydrofolate reductase inhibitor, metoprine, expressed increased levels of one-carbon, reduced folate transport inward (Sirotnak, F. M., Moccio, D.

Rapid decline in folylpolyglutamate synthetase activity and gene expression during maturation of HL-60 cells. Nature of the effect, impact on folate compound polyglutamate pools, and evidence for programmed down-regulation during maturation.

These studies in HL-60 cells examined the regulation of folylpolyglutamate synthetase (FPGS) activity at the level of gene expression during terminal maturation. Following addition of 210 mM Me2SO to cultures of HL-60 cells at a concentration that induces maturation of 85-90% of the cells, FPGS activity, but not folylpolyglutamate hydrolase (FPGH) activity, was reduced 2-7-fold within 1-5 days. The initial decline in FPGS activity preceded any effect of Me2SO on rate of growth and the increase in appearance of nitro blue tetrazolium-positive cells, a marker of cellular maturation, and the decrease after 5 days of exposure to Me2SO was solely accounted for by a 7-fold decrease in value for Vmax.

Coombs-positive autoimmune hemolytic anemia and postinfantile giant cell hepatitis in children.

We report a 23-month-old girl and a 9-month-old boy who presented with autoimmune hemolytic anemia followed by recurrent episodes of severe hepatitis. The first episode of hepatitis occurred 1 week and 15 months after presentation, respectively. Histologically, the livers showed loss of lobular architecture with diffuse giant cell transformation of hepatocytes and portal and pericellular fibrosis.

Analysis of three distinct Ly6-A-related cDNA sequences isolated from rat kidney.

Mouse Ly6A and Ly6C cDNA probes were hybridized to total RNA of rat tissues and, as in mouse, the highest level of Ly6-related transcripts was detected in kidney. Therefore, Ly6-related cDNA clones were isolated from a commercial rat kidney cDNA library in lambda gt11. Four of these (RK3, RK6, RK10, and RK11) have been fully characterized, and represent transcripts from three distinct genes.