Disease relevance of YAP1

• The cadmium hypersensitivity of the delta yap1 mutant described here indicates that one major role of YAP1 in the yeast cell is to mediate resistance to this metal [1].
• Thus, Yap1 is not directly involved in SRP1 induction by hypoxia, but is necessary to counteract the Ord1 effect [2].
• Since ABC transporters are YAP1p transcription activator inducible, we included a yap1 mutant in our Sn2+ toxicity assay [3].

High impact information on YAP1

• When oxidized by H2O2, Gpx3 Cys36 bridges Yap1 Cys598 by a disulfide bond [4].
• We identified the glutathione peroxidase (GPx)-like enzyme Gpx3 as a second component of the pathway, serving the role of sensor and transducer of the hydroperoxide signal to Yap1 [4].
• The Yap1 transcription factor regulates hydroperoxide homeostasis in S. cerevisiae [4].
• PAR-1 protein is localized to the posterior periphery of the zygote and is distributed in a polar fashion preceding the asymmetric divisions of the germline lineage [5].
• The same DNA microarrays were also used to identify genes whose expression was affected by deletion of the transcriptional co-repressor TUP1 or overexpression of the transcriptional activator YAP1 [6].

Chemical compound and disease context of YAP1

• Although the c-CRD mutant forms of Yap1p activate an artificial Yap1p-responsive gene to the same high level in the presence of either diamide or H(2)O(2), these mutant factors confer hyperresistance to diamide but hypersensitivity to H(2)O(2) [7].
• Finally, we show that FLR1 overexpression confers resistance to diamide, diethylmaleate, and menadione but hypersensitivity to H(2)O(2), demonstrating that the Flr1p transporter participates in Yap1p-mediated oxidative stress response in S. cerevisiae [8].
• In this study, we show that overexpression of Yap1 complemented the arsenite hypersensitivity of the ycf1 null mutant, but only if the ACR3 gene is functional [9].

Biological context of YAP1

• Changes in gene dosage of the YAP1 gene, encoding the yAP-1 transcriptional regulatory protein, cause profound alterations in cellular drug and metal resistance [10].
• Strains lacking the YAP1 or GCN4 structural gene have very different phenotypes, which have been taken as evidence that these transcriptional regulatory proteins control separate batteries of target genes [11].
• Taken collectively, our results demonstrate that FLR1 represents a new YAP1-controlled multidrug resistance molecular determinant in S. cerevisiae [12].
• The role of the YAP1 and YAP2 genes in the regulation of the adaptive oxidative stress responses of Saccharomyces cerevisiae [13].
• Whereas a Yap1p-responsive lacZ fusion gene was oxidant inducible in the presence of YAP1, the C. albicans Cap1p derivatives were not oxidant responsive in S. cerevisiae [14].

Anatomical context of YAP1

• We have found that YAP1-mediated diazaborine resistance in the yeast Saccharomyces cerevisiae requires two efflux pumps, i.e. the major-facilitator-superfamily transporter Flr1p, which is located in the cytoplasmic membrane and the ATP-binding-cassette transporter Ycf1p which is present in the vacuolar membrane [15].
• In this report, we identify naturally occurring nucleotide sequences that function as internal ribosome entry sites (IRESes) within the 5' leader sequences of Saccharomyces cerevisiae YAP1 and p150 mRNAs [16].

Associations of YAP1 with chemical compounds

• Within the bZIP domain, ACR1 most strongly resembles the mammalian cyclic AMP-responsive transcriptional regulators CREB and CREM; it is less similar to GCN4 and YAP1, two previously described yeast bZIP transcriptional activators that recognize the related AP-1 sequence (consensus TGACTCA) [17].
• YAP1 encodes a positive regulator with a leucine zipper motif that causes pleiotropic drug resistance when overproduced [18].
• This allele of YAP1 carries a mutation that leads to a C620F exchange in the C-terminal cysteine-rich-domain region and is the first mutant of YAP1 that was isolated by a conventional genetic screen for drug resistance [15].
• YAP1 was able to mediate both cadmium- and H2O2-induced transcriptional activation of an ARE-dependent promoter [19].
• YAP1 confers resistance to the fatty acid synthase inhibitor cerulenin through the transporter Flr1p in Saccharomyces cerevisiae [20].

Physical interactions of YAP1

• In an in vitro assay, we showed that Yap1p could directly bind to Pse1p and that this interaction was dissociated by Ran-GTP [21].
• The RPN4 promoter contains an additional sequence that binds Yap1p, a bZIP-type transcription factor that plays an important role in the oxidative stress response and multidrug resistance [22].
• DNA-affinity blots of proteins from YAP1 cells suggest the presence of additional TGACTCA-binding proteins other than GCN4 and yAP-1 [23].
• Multiple Yap1p-binding sites mediate induction of the yeast major facilitator FLR1 gene in response to drugs, oxidants, and alkylating agents [8].
• Indeed, Ybp1 forms a stress-induced complex with Yap1 in vivo and stimulates the nuclear accumulation of Yap1 in response to H2O2 but not in response to the thiol-oxidizing agent diamide [24].
• In the present study, we show that Tsa1 can interact with Yap1 via disulfide linkages and induce the formation of intramolecular disulfide bonds in Yap1 in ybp1-1 cells [25].

Regulatory relationships of YAP1

• Expression of ATR1 is enhanced in the presence of constitutively active alleles of YAP1 and GCN4 [11].
• The expression of GSH1 in Saccharomyces cerevisiae has been known to be up-regulated by Yap1p, a critical transcription factor for the oxidative stress response in yeast [26].
• The present study demonstrates that GSH2 expression is also regulated by Yap1p under oxidative stress-induced conditions [26].
• In addition, TSA2 was activated in tsa1Delta cells in a Yap1p-dependent manner [27].
• Transcription of YHB1 is not under the control of the transcriptional factor Yap1p [28].

Other interactions of YAP1

• Northern (RNA) blot analysis showed that GSH1 mRNA levels were responsive to YAP1 gene dosage [10].
• Nuclear import of the yeast AP-1-like transcription factor Yap1p is mediated by transport receptor Pse1p, and this import step is not affected by oxidative stress [21].
• The GPX2 gene expression was induced by oxidative stress, which was dependent upon the Yap1p [29].
• We have found a new hypoxic pathway involving an antagonistic interaction between the Ixr1/Ord1 repressor and the Yap1 factor, a transcriptional activator involved in oxidative stress response [2].
• The correlation between H(2)O(2) sensitivity and the accumulation of oxidized proteins was evaluated by assaying protein carbonyls in mutants deficient in the stress response regulators Yap1p and Skn7p [30].

Analytical, diagnostic and therapeutic context of YAP1

• The respective roles of Yap1 and Skn7 in the induction of defense genes by H2O2 were analyzed by two-dimensional gel electrophoresis [31].
• Sequence analysis of the mutant yap1 genes revealed three point mutations and two truncation mutations near the carboxy-terminus [32].
• Gel retardation assays confirmed that Yap1p differentially binds to the three YREs (YRE3 > YRE2 > YRE1) [8].
• Discrimination between paralogs using microarray analysis: application to the Yap1p and Yap2p transcriptional networks [33].
• Northern blot and whole-genome expression analysis revealed that the basal expression of most Yap1p targets and many other H2O2-inducible genes is elevated in Deltatrr1 mutants in the absence of external stress [34].

References