Cadmium is an environmental contaminant that is both a human toxicant and carcinogen. To inhibit cadmium-induced damage, cells respond by increasing the expression of genes that encode stress-response proteins. We previously reported the identification of 48 cadmium-inducible mRNAs in the nematode Caenorhabditis elegans. Here we describe a new cadmium-responsive gene, designated cdr-1, whose rate and level of inducible expression parallel those of the C. elegans metallothioneins. The CDR-1 mRNA contains an open reading frame of 831 bp and encodes a predicted 32-kDa, integral membrane protein. Following cadmium exposure, cdr-1 is transcribed exclusively in intestinal cells of post-embryonic C. elegans. In vivo, the CDR-1 protein is targeted specifically to the intestinal cell lysosomes. cdr-1 transcription is significantly induced by cadmium but not by other tested stressors. These results indicate that cdr-1 expression is regulated by cadmium and in a cell-specific fashion. Inhibition of CDR-1 expression renders C. elegans susceptible to cadmium toxicity. In conclusion, cdr-1 defines a new class of cadmium-inducible genes and encodes an integral membrane, lysosomal protein. This protein functions to protect against cadmium toxicity.The transition metal cadmium is considered a serious occupational and environmental health threat. It is continuously introduced into the atmosphere through the smelting of ores and the burning of fossil fuels and is commonly found in "Superfund" clean-up sites (1-3). Humans are exposed to cadmium primarily via inhalation and the ingestion of cadmium-containing foods (4). Toxicological responses of cadmium exposure include kidney damage, respiratory diseases, neurological disorders, and lung, kidney, prostate, and testicular cancers (4).Cadmium induces intracellular damage via the (a) nonspecific inactivation/denaturation of proteins, by binding to free sulfhydryl residues; (b) displacement of zinc co-factors from a variety of proteins, including transcription factors; and (c) generation of reactive oxygen species, which ultimately oxidize DNA, proteins, and lipids. Although cadmium itself is not redox active in vivo and cannot directly catalyze the reduction of molecular oxygen, it has been suggested that the production of reactive oxygen species is a consequence of a cadmium-induced depletion of cellular glutathione or the inactivation of copper/ zinc-superoxide dismutase (5, 6).To attenuate the toxic effects of cadmium, cells respond by increasing the steady-state levels of a variety of proteins. The functions of these proteins can be broadly defined, because those that repair intracellular damage or those that remove the toxicants (e.g. cadmium, reactive oxygen species). To remove toxicants, cells activate the transcription of genes that encode proteins that are involved in scavenging reactive oxygen species, including heme oxygenase, ␥-glutamylcysteine synthetase, superoxide dismutase, catalase, glutathione peroxidase, and glucose-6-phosphate dehydrogenase (7-11). Cadmium is esse...
