METALLOTHIONEIN-I AND METALLOTHIONEIN-II KNOCK-OUT MICE ARE SENSITIVETO CADMIUM-INDUCED LIVER MESSENGER-RNA EXPRESSION OF C-JUN AND P53

Zinc pretreatment has been shown in vitro (rat myoblasts) to induce me tallothionein (MT) and inhibit cadmium (Cd)-induced protooncogenes c-m yc and c-jun mRNA levels. Therefore, the purpose of this study was to determine whether the mRNA expression of the protooncogene c-jun as we ll as the tumor suppressor gene p53 is increased by Cd in the intact a nimal and, more specifically, in the target organ for Cd toxicity, the liver. Additionally, modulation of the expression of these genes was investigated in the absence of MT. The effect of CdCl2 on the mRNA lev els of c-jun and p53 was studied in livers of C57BL/6J (control) and M T-null mice by Northern- and slot-blot analyses. The mRNA for c-jun an d p53 were increased by Cd in a dose-dependent fashion. In the control mice, Cd induced c-jun mRNA (5-fold) at 3 and 12 hr and p53 mRNA (1.8 - to 2-fold) at 6 and 12 hr. Compared to controls, the MT-null mice we re more sensitive to the Cd-induced gene expression. The magnitude of the inductions was more pronounced and the elevated mRNA levels of c-j un and p53 were seen at lower doses of Cd (10 mu mol/kg in MT-null mic e vs 40 mmol/kg in control mice). In conclusion, these data demonstrat e that Cd induces mRNA expression of the protooncogene c-jun and tumor suppressor gene p53 in liver, and that MT modulates this effect. (C) 1996 Academic Press, Inc.