Disease relevance of CAD1

• The KlYAP1 gene, encoding the transcription factor Yap1p from Kluyveromyces lactis, was cloned by functional complementation of the cadmium hypersensitivity phenotype of a Saccharomyces cerevisiae strain lacking functional YAP1 and YAP2 genes [1].

High impact information on CAD1

• Moreover, mutants in the proteasome are hypersensitive to cadmium, suggesting that cadmium resistance is mediated in part by degradation of abnormal proteins [2].
• Our data explain the destabilizing properties of YAP2-type uORFs and also support a more general model for the mode of action of other known uORFs, such as those in the GCN4 mRNA [3].
• Release of post-termination ribosomes from the YAP2 5'UTR causes accelerated decay which is largely independent of the termination modulator gene UPF1 [3].
• The 5' untranslated region (5'UTR) of the Saccharomyces cerevisiae gene encoding the AP1-like transcription factor Yap2 contains two upstream open reading frames (uORF1 and uORF2) [3].
• The YAP2-type of uORF functions as a cis-acting element that attenuates gene expression at the level of mRNA turnover via termination-dependent decay [3].

Biological context of CAD1

• In this study, we demonstrated that the yap1 disruptant is also unable to grow in medium containing 150 microM cadmium, whereas the yap2 disruptant exhibited no significant phenotypes [4].
• Stress-induced transcriptional activation mediated by YAP1 and YAP2 genes that encode the Jun family of transcriptional activators in Saccharomyces cerevisiae [4].
• A high-copy-number plasmid bearing YAP2 mediated cadmium-induced transcriptional activation of this promoter [4].
• These effects depended on the YAP1 and CAD1/YAP2 gene dosage [5].
• Yap2 is normally cytoplasmic, but rapidly migrates to the nucleus upon exposure to oxidative stress agents [6].

Anatomical context of CAD1

• Whether CAD1/AAF1 contributes to the adherence of C. albicans to endothelial cells remains to be determined [7].
• Consistent with this finding, immunoelectron microscopy revealed that CAD1/AAF1 localized to the cytoplasm and nucleus but not the cell wall or plasma membrane of the transformed yeasts [7].
• Their particular intracellular localization suggests that chloroplasts may play a major role in the cadmium-resistance mechanism in organisms lacking a plant-like vacuole [8].

Associations of CAD1 with chemical compounds

• Yap-dependent transcription is abolished in strains containing high levels of protein kinase A; in contrast, Gcn4 transcriptional activity is stimulated by protein kinase A. Interestingly, Yap1 transcriptional activity is stimulated by hydrogen peroxide, whereas Yap2 activity is stimulated by aminotriazole and cadmium [9].
• Differential effect of cysteine-to-serine substitutions in metallothionein on cadmium resistance [10].
• Our results indicate that yeast YCF1 is a glutathione S-conjugate pump, like MRP, and they raise the possibility that the cadmium resistance in yeast involves cotransport of cadmium with glutathione derivatives [11].
• On the other hand, L0 is required for transport function, as determined by monitoring cadmium resistance [12].
• This screening process yielded a small Cys-rich membrane protein (Arabidopsis plant cadmium resistance, AtPcrs) [13].

Other interactions of CAD1

• However, YAP2 in high copy number did suppress cadmium sensitivity, but not H2O2 sensitivity of the yap1 disruptant [4].
• The Saccharomyces cerevisiae YAP2 gene encoding an AP-1-like transcriptional activator protein was cloned by selection for genes that confer pleiotropic drug resistance when present in high copy number [4].
• The SLC1 gene lies adjacent to the YAP2 (= CAD1) transcription unit [14].
• In a fraction of untreated pbs2 cells, Yap2 is nuclear [6].
• Such a specialization may explain, at least in part, the dissociated function of Yap1 and Skn7 in H2O2 and cadmium resistance [15].

Analytical, diagnostic and therapeutic context of CAD1

• We conclude that while Yap1p and Yap2p may have some overlapping functions they are clearly not redundant and, more generally, that DNA microarray analysis will be an important tool for distinguishing the functions of the large numbers of highly conserved genes found in all eukaryotic genomes [16].
• Discrimination between paralogs using microarray analysis: application to the Yap1p and Yap2p transcriptional networks [16].
• By site-directed mutagenesis, it appeared that the mutation conferring cadmium resistance was a R970G-substitution in the C-terminal region of Pca1 protein [17].

References