The SNQ3 gene of Saccharomyces cerevisiae confers hyper-resistance to several functionally unrelated chemicals

Hertle, Karin; Haase, Eckard; Brendel, Martin

doi:10.1007/bf00312733

Cited by 76 publications

(38 citation statements)

References 47 publications

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“…Yap1 was first identified and cloned on the basis of its ability to bind to an SV40 AP-1 recognition element (TTAGTCA) (Moye-Rowley et al 1989), but has subsequently been cloned on three separate occasions based on its capacity, when overexpressed, to confer resistance to a variety of cytotoxic compounds. Thus, the YAP1 gene also goes by the gene names PDR4 (pleiotropic drug resistance) because overexpression results in resistance to sulphometuron methyl and cycloheximide (Hussain & Lenard 1991), SNQ3, based on its ability to confer resistance to 4-nitroquinoline-N-oxide (Hertle et al 1991) and PAR1 because it confers resistance to the iron chelators 1,10-phenanthroline and 1-nitroso-2-napthol (Schnell & Entian 1991). Deletion of YAP1 results in hypersensitivity to oxidative stress, cadmium toxicity and treatment with the drug cycloheximide (Schnell et al 1992;Kuge & Jones 1994); thus Pap1 in fission yeast and Yap1 in budding yeast appear to have very similar roles in mediating stress responses.…”

Section: Atf1 and Pap1 Mediate Sty1 Regulation Of Transcriptionmentioning

confidence: 99%

Stress‐activated signalling pathways in yeast

1998

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Eukaryotic cells have developed response mechanisms to combat the harmful effects of a variety of stress conditions. In the majority of cases, such responses involve changes in the gene expression pattern of the cell, leading to increased levels and activities of proteins that have stress-protective functions. Over the last few years, considerable progress has been made in understanding how stress-dependent transcriptional changes are brought about, and it transpires that the underlying mechanisms are highly conserved, being similar in organisms ranging from yeast to man. Many of the stress signals derive from the extracellular environment and accordingly these signals require transduction from the cell surface to the nucleus. This is accomplished through stress-activated signalling pathways, key amongst which are the highly conserved stress-activated MAP kinase pathways. Stimulation of these pathways leads to the increased activity of specific transcription factors and consequently the increased expression of certain stress-related genes. In this review, we focus on the progress that has been made in understanding these stress responses in yeast.

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Section: Atf1 and Pap1 Mediate Sty1 Regulation Of Transcriptionmentioning

confidence: 99%

Stress‐activated signalling pathways in yeast

1998

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“…However, in comparison to conventional AP-1 factors, we have noticed that Yap1 and Yap2 differ at two of the five highly conserved residues that directly contact bases in the AP-1 site (see Results). Overexpression of Yap1 or Yap2 leads to increased resistance to a variety of drugs and metals (5,16,18,21,51,65), with Yap1 typically having stronger effects. Both Yap1 and Yap2 can stimulate transcription from an artificial promoter containing a simian virus 40 (SV40) sequence (TG ACTAA) that differs from the optimal AP-1 site by a single base pair.…”

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Yap, a Novel Family of Eight bZIP Proteins in Saccharomyces cerevisiae with Distinct Biological Functions

Fernandes

Rodrigues-Pousada

Struhl

1997

Molecular and Cellular Biology

294

316

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Saccharomyces cerevisiae contains eight members of a novel and fungus-specific family of bZIP proteins that is defined by four atypical residues on the DNA-binding surface. Two of these proteins, Yap1 and Yap2, are transcriptional activators involved in pleiotropic drug resistance. Although initially described as AP-1 factors, at least four Yap proteins bind most efficiently to TTACTAA, a sequence that differs at position ؎2 from the optimal AP-1 site (TGACTCA); further, a Yap-like derivative of the AP-1 factor Gcn4 (A239Q S242F) binds efficiently to the Yap recognition sequence. Molecular modeling suggests that the Yap-specific residues make novel contacts and cause physical constraints at the ؎2 position that may account for the distinct DNA-binding specificities of Yap and AP-1 proteins. To various extents, Yap1, Yap2, Yap3, and Yap5 activate transcription from a promoter containing a Yap recognition site. 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. In addition, unlike other yap mutations tested, yap4 (cin5) mutations affect chromosome stability, and they suppress the cold-sensitive phenotype of yap1 mutant strains. Thus, members of the Yap family carry out overlapping but distinct biological functions.

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“…While this biochemical similarity allowed the isolation of the YAP1 gene, the function of the yeast protein was initially difficult to assess. Work from a variety of laboratories has since shown that high-copy-number plasmids carrying the YAP] gene provide dramatic increases in resistance to drugs such as sulfometuron methyl, cycloheximide, 1,10-phenanthroline, 4-nitroquinoline, and cadmium (3,8,16,27,35). Strains lacking a functional YAP1 allele are hypersensitive to oxidative stress (27), 4-nitroquinoline (8), and cadmium (35).…”

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GSH1, which encodes gamma-glutamylcysteine synthetase, is a target gene for yAP-1 transcriptional regulation.

1994

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Changes in gene dosage of the YAP) gene, encoding the yAP-1 transcriptional regulatory protein, cause profound alterations in cellular drug and metal resistance. Previous studies on yAP-1 action in yeast cells have used the AP-1 response element (ARE) from simian virus 40 as an artificial site for yAP-i-mediated transcriptional activation. No authentic yeast target sites for control of gene expression by yAP-i are known.Here we show that the GSHI gene, encoding y-glutamylcysteine synthetase, is transcriptionally responsive to the yAP-i protein. GSHI encodes the rate-limiting step in yeast glutathione biosynthesis and contains within its promoter region a DNA element that matches the ARE in 11 of 12 positions. The GSHI yAP-i response element (YRE) was recognized by yAP-i protein in vitro. Northern (RNA) blot analysis showed that GSHI mRNA levels were responsive to YAP) gene dosage. A site-directed mutation in the YRE that blocked yAP-1 binding in vitro prevented the mutant GSHI promoter from responding to elevation in YAP] gene dosage. A Agshl mutant strain was constructed and unable to grow in the absence of exogenous glutathione. A mutant GSHI gene lacking the YRE was unable to confer normal cadmium tolerance, although other yAP-i-mediated phenotypes remained normal. Thus, GSHI is one of several genes that are transcriptionally controlled by yAP-i and influence drug resistance.The Saccharomyces cerevisiae AP-1 protein (yAP-1) was originally identified as a biochemical homolog of mammalian 13). While this biochemical similarity allowed the isolation of the YAP1 gene, the function of the yeast protein was initially difficult to assess. Work from a variety of laboratories has since shown that high-copy-number plasmids carrying the YAP] gene provide dramatic increases in resistance to drugs such as sulfometuron methyl, cycloheximide, 1,10-phenanthroline, 4-nitroquinoline, and cadmium (3,8,16,27,35). Strains lacking a functional YAP1 allele are hypersensitive to oxidative stress (27), 4-nitroquinoline (8), and cadmium (35). Clearly, changes in the copy number of the YAP] gene have pronounced effects on the ability of yeast cells to tolerate drug challenges.While a wide variety of phenotypes that are associated with yAP-1 have been found, none of these phenotypes are thought to be a consequence of the direct action of this factor. The phenotypic influence of yAP-1 on cells is believed to be mediated via this protein acting as a transcriptional regulatory molecule. We have found that mutations in the YAP] gene that inactivate the ability of the gene product to serve as a positive regulator of transcription also block the normal appearance of drug resistance mediated by yAP-1 (34). Thus, the effects of yAP-1 on drug resistance are likely to be mediated by the products of yAP-1-regulated genes. The large number of phenotypes produced by changes in YAP] gene dosage suggests that several different genes are under of yAP-1 control. However, no yAP-1 target gene has yet been identified.In the work described here, we find th...

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The SNQ3 gene of Saccharomyces cerevisiae confers hyper-resistance to several functionally unrelated chemicals

Cited by 76 publications

References 47 publications

Stress‐activated signalling pathways in yeast

Stress‐activated signalling pathways in yeast

Yap, a Novel Family of Eight bZIP Proteins in Saccharomyces cerevisiae with Distinct Biological Functions

GSH1, which encodes gamma-glutamylcysteine synthetase, is a target gene for yAP-1 transcriptional regulation.

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