YEAST BZIP PROTEINS MEDIATE PLEIOTROPIC DRUG AND METAL RESISTANCE

Saccharomyces cerevisiae contains a group of transcription factors rel ated to mammalian c-Jun. This yeast Jun-family of proteins consists of GCN4, a regulator of genes involved in amino acid biosynthesis, and y AP-1, a factor conferring pleiotropic drug resistance when overexpress ed. In the work described here, we show that a third member of the yea st Jun-family exists. This protein has been designated CAD1 and provid es resistance to cadmium when present on a high-copy plasmid. CAD1 and yAP-1 are related in their amino-terminal DNA binding domains and can recognize the same DNA target site in vitro. Overproduction of CAD1 l eads to transcriptional activation of an artificial reporter gene in D ELTAyap1 cells. High level production of either CAD1 or yAP-1 causes c ells to acquire a pleiotropic drug-resistant phenotype and to be able to tolerate normally toxic levels of iron chelators and zinc. Surprisi ngly, disruption of the CAD1 gene has no effect on the normal cellular resistance to cadmium but DELTAyap1 mutants are hypersensitive to thi s cytotoxic metal. The cadmium hypersensitivity of the DELTAyap1 mutan t described here indicates that one major role of YAP1 in the yeast ce ll is to mediate resistance to this metal.