New mouse somatic cell mutants resistant to cadmium affected in the expression of their metallothionein genes

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Abstract
Fluctuation tests à la Luria and Delbruck were performed with mouse LMTK cells, and the results indicate that the appearance of variants resistant to cadmium is due to random spontaneous mutations and not to epigenetic events. The rate of spontaneous mutations leading to cadmium resistance was calculated to be 0.92 × 10−6 per cell per generation. This rate increased 14-fold on treatment with ethyl methane sulfonate. Several stable mutant cell lines resistant to cadmium were selected and characterized with respect to metallothionein (MT) induction. Based on the copy number of mt+ genes and the levels of MT proteins and mRNA, the mutants could be divided into two classes, A and B. Although group A mutants have the same number of mt1+ and mt2+genes as wild-type cells, upon induction with cadmium, the amount of MT proteins and mRNA in the mutants are greatly increased over wild-type levels. This observation strongly suggests a mutation that regulates MT gene transcription in these cells. In group B mutants, the mt+genes are amplified about three- to fourfold, and their MT protein and mRNA basal levels are, as expected, much higher than in the wild-type cells, under uninduced and induced conditions.