RELATIONSHIP BETWEEN CADMIUM-INDUCED EXPRESSION OF HEATSHOCK GENES, INHIBITION OF PROTEIN-SYNTHESIS AND CELL-DEATH

Stress proteins (heat shock proteins, HSPs) have been proposed as mark ers for toxicity. This study has focussed on the pattern of HSP synthe sis in relation to cytotoxicity and their dependence on doses of cadmi um chloride. We investigated the relationship between cadmium-induced expression of heatshock genes, inhibition of protein synthesis and cel l death in a well-differentiated hepatoma cell line, Reuber H35, under exposure conditions ranging to full (> 98%) lethality. We find a non- linearity in the responses of these cells when the duration of cadmium exposure is varied. The results indicate that sublethal concentration s of cadmium can inhibit protein synthesis and also increase the synth esis of certain HSPs. The pattern of heat shock protein induction chan ges when exposure conditions become more severe. The most strongly ind ucible heat shock protein, HSP68, is, surprisingly, only synthesized u nder conditions which lead to severe inhibition of protein synthesis. The comparison of HSP68 mRNA levels and HSP68 synthesis showed that HS P68 mRNA is already induced under conditions where the synthesis of HS P68 protein cannot yet be traced. From these data we conclude that a d ifferential HSP expression takes place. The translational control of H SP synthesis might be explained by the preferential translation of thi s mRNA under conditions of severe shut-off of general protein synthesi s.