Multidrug-Resistant Transport Proteins in Yeast: Complete Inventory and Phylogenetic Characterization of Yeast Open Reading Frames within the Major Facilitator Superfamily

Goffeau, André; Park, Jay; Paulsen, Ian T.; Jonniaux, Jean-Luc; Dinh, Thien; Mordant, P.; Saier, Milton H.

doi:10.1002/(sici)1097-0061(199701)13:1<43::aid-yea56>3.0.co;2-j

Cited by 137 publications

(94 citation statements)

References 44 publications

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“…which were proposed to be integral membrane proteins and conducive to resistance phenotypes when present in multicopies (40 -43). These proteins belong to either the ABC (ATPbinding cassette) family or the MFS (major facilitator superfamily) family (43)(44)(45). The putative Acr3p, lacking ATPbinding cassette, may belong to the MFS superfamily.…”

Section: Discussionmentioning

confidence: 99%

“…The putative Acr3p, lacking ATPbinding cassette, may belong to the MFS superfamily. However, the Acr3p is not present in the group of 100 S. cerevisiae transport proteins classified as the MFS proteins (43)(44)(45). MFS proteins comprise 500 -600 amino acids with 12 transmembrane helices and share sequence similarities suggesting the common ancestral origin (43)(44)(45).…”

Section: Discussionmentioning

confidence: 99%

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The Saccharomyces cerevisiae ACR3 Gene Encodes a Putative Membrane Protein Involved in Arsenite Transport

Wysocki

Bobrowicz

Ułaszewski

1997

Journal of Biological Chemistry

225

197

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The cluster of three genes, ACR1, ACR2, and ACR3, previously was shown to confer arsenical resistance in Saccharomyces cerevisiae. The overexpression of ACR3 induced high level arsenite resistance. The presence of ACR3 together with ACR2 on a multicopy plasmid was conducive to increased arsenate resistance. The function of ACR3 gene has now been investigated. Amino acid sequence analysis of Acr3p showed that this hypothetical protein has hydrophobic character with 10 putative transmembrane spans and is probably located in yeast plasma membrane. We constructed the acr3 null mutation. The resulting disruptants were 5-fold more sensitive to arsenate and arsenite than wild-type cells. The acr3 disruptants showed wild-type sensitivity to antimony, tellurite, cadmium, and phenylarsine oxide. The mechanism of arsenical resistance was assayed by transport experiments using radioactive arsenite. We did not observe any significant differences in the accumulation of 76 AsO 3 3؊ in wild-type cells, acr1 and acr3 disruptants. However, the high dosage of ACR3 gene resulted in loss of arsenite uptake. These results suggest that arsenite resistance in yeast is mediated by an arsenite transporter (Acr3p).Arsenicals are toxic compounds, which are commonly present in the environment at increasing concentrations as a result of industrial pollution (1). The pentavalent arsenate is a phosphate analog which interferes with phosphorylation reactions and competes with phosphate in transport (2-4). The more potent trivalent arsenite reacts with the sulfhydryl groups of proteins and inhibits many biochemical pathways (3, 5). Both arsenic salts were observed to induce morphological transformation and some cytogenetic effects (6 -8).Arsenical resistance phenomenon was described in many organisms from bacteria to mammalian cells (9 -13). Resistance to arsenate, arsenite, and antimonite in prokaryota is mediated by a plasmid-encoded transport system (14 -16). The Escherichia coli ars operon located on the plasmid R773 consists of five genes : arsR, arsD, arsA, arsB, and arsC (14, 17). The arsR and arsD encode trans-acting regulatory proteins (17,18). The products of arsA and arsB genes are the two subunits of an ATP-coupled oxyanion pump (14). The ArsA protein is the catalytic subunit exhibiting an ATPase activity (19). The ArsB protein is an inner membrane component of the pump (20), which acts as an anion channel and an anchor for the ArsA protein (21). The arsC gene was shown to encode an arsenate reductase (22). Similar ars operons were identified in Grampositive bacteria: Staphylococcus aureus (pI258) (15) and Staphylococcus xylosus (pSX267) (16). In staphylococcal ars operons arsR, -B, -C genes are conserved but arsD and arsA are absent. In this case arsenite efflux is mediated only by the ArsB protein coupled to the protonmotive force (23). Arsenical resistance in eukaryotic cells is also transport-mediated (4, 11, 13, 24). The existence of an energy-dependent arsenical efflux pump was demonstrated in Leishmania tarentolae (24, 25) an...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The Saccharomyces cerevisiae ACR3 Gene Encodes a Putative Membrane Protein Involved in Arsenite Transport

Wysocki

Bobrowicz

Ułaszewski

1997

Journal of Biological Chemistry

225

197

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“…This process has been extensively studied in the yeast Saccharomyces cerevisiae. Two major classes of multidrug transporters have been identified: the major facilitator superfamily (MFS) 1 (1) and the ABC (ATP binding cassette) family of transporters (2)(3)(4). ABC transporters act in an ATP-dependent manner, and their overexpression leads to increased drug resistance.…”

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confidence: 99%

Zinc Cluster Protein Rdr1p Is a Transcriptional Repressor of the PDR5 Gene Encoding a Multidrug Transporter

Hellauer¹,

Akache²,

MacPherson³

et al. 2002

Journal of Biological Chemistry

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The yeast PDR5 gene encodes an efflux pump that confers multidrug resistance. Expression of PDR5 is positively regulated by the transcription factors Pdr1p and Pdr3p that recognize the same pleiotropic drug resistance elements (PDREs) in the PDR5 promoter. Pdr1p and Pdr3p belong to the Gal4p family of zinc cluster proteins. The function of RDR1 (YOR380W), which also encodes a member of this family, is unknown. To identify target genes for Rdr1p, we have performed wholegenome analysis of gene expression with DNA microarrays. Our results show that Rdr1p is a transcriptional repressor of five genes, including PDR5. A ⌬rdr1 strain has increased resistance to cycloheximide, as expected from the overexpression of PDR5. In addition, the activity of a PDR5-lacZ reporter is increased in a ⌬rdr1 strain. All (but one) genes affected by removal of Rdr1p contain PDREs in their promoters. We tested if the effect of Rdr1p is mediated through PDREs by inserting this DNA element in front of a minimal promoter. Activity of this reporter was increased in a ⌬rdr1 strain. Moreover, mutations known to reduce binding of Pdr1/ Pdr3p abolished the induction observed in the ⌬rdr1 strain. Thus, we have identified a transcriptional repressor involved in the control of multidrug resistance.Multidrug resistance is a widespread phenomenon that allows organisms ranging from bacteria to humans to defend themselves against a variety of toxic compounds. Drug resistance is mediated through membrane-bound transporters that act as drug efflux pumps. This process has been extensively studied in the yeast Saccharomyces cerevisiae. Two major classes of multidrug transporters have been identified: the major facilitator superfamily (MFS) 1 (1) and the ABC (ATP binding cassette) family of transporters (2-4). ABC transporters act in an ATP-dependent manner, and their overexpression leads to increased drug resistance. Members of the family of ABC transporters include Pdr5p, Snq2p, and Yor1p (2).The transcriptional activators Pdr1p and Pdr3p control the expression of many ABC transporters (3, 4). These activators belong to a family of transcriptional regulators called zinc cluster or binuclear cluster proteins (5-7). Members of this family contain six highly conserved cysteines that coordinate binding to two zinc atoms to allow proper folding of the DNA binding domain. The cysteine-rich region (or zinc finger) is usually followed by a short linker sequence that bridges the zinc finger to a dimerization domain (6). This domain is involved in recognition of specific DNA sequences through interaction of the zinc finger with DNA (for references see Ref. 8). Pdr1p and Pdr3p both recognize CGG triplets oriented in opposite directions (CCGCGG) to form an everted repeat (9). This motif is found in the target genes of Pdr1p and Pdr3p (10 -17). For example, three binding sites called PDREs (pleiotropic drug response elements) for Pdr1p and Pdr3p have been mapped in the PDR5 promoter (10, 12). Thus, Pdr1p and Pdr3p recognize the same DNA sequences in target promoters f...

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“…Usually they are associated with either transmembrane proteins, which contain ATP binding cassette(s) (ABC), or members of the major facilitator system (MFS) families. The ubiquitous occurrence and close similarity of the identified proteins reflect the importance of these protein families (for review, see Goffeau et al, 1997). The genome sequence from S. cerevisiae has revealed the presence of as many as 28 ORFs homologous to either the ABC or the MFS family (Goffeau et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

“…The ubiquitous occurrence and close similarity of the identified proteins reflect the importance of these protein families (for review, see Goffeau et al, 1997). The genome sequence from S. cerevisiae has revealed the presence of as many as 28 ORFs homologous to either the ABC or the MFS family (Goffeau et al, 1997). Yeast multidrug transporters include the ABCs protein CDR1-3 from Candida albicans (Sanglard et al, 1997;Balan et al, 1997) and the MSF BEN r (CaMDR1) that renders cells resistant to cyh, benomyl, methotrexate, 4-nitro-quinoline-N-oxide, or terbinafine (Ben-Yaacov et al, 1994;Goldway et al, 1995;Sanglard et al, 1997;Gupta et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

The SCR1 gene from Schwanniomyces occidentalis encodes a highly hydrophobic polypeptide, which confers ribosomal resistance to cycloheximide

Hoenicka

Lobato

Marín

et al. 2002

Yeast

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In Saccharomyces cerevisiae, the SCR1 gene from Schwanniomyces occidentalis is known to induce ribosomal resistance to cycloheximide (cyh). A 2.8 kb DNA fragment encoding this gene was sequenced. Its EMBL Accession No. is AJ419770. It disclosed a putative tRNA Asn (GUU) sequence located downstream of an open reading frame (ORF) of 1641 nucleotides. This ORF was shown to correspond to SCR1. It would encode a highly hydrophobic polypeptide (SCR1) with 12 transmembrane domains. SCR1 is highly similar to a variety of yeast proteins of the multidrug-resistance (MDR) family. However, SCR1 only conferred resistance to cyh but not to benomyl or methotrexate. The cyh-resistance phenotype induced by SCR1 was confirmed in several S. cerevisiae strains that expressed this gene to reside at the ribosomal level. In contrast, a b-galacosidase-tagged SCR1 was found to be integrated in the endoplasmic reticulum (ER). It is proposed that the ribosomes of yeast cells expressing SCR1 undergo a conformational change during their interaction with the ER, which lowers their affinity for cyh-binding. If so, these findings would disclose a novel ribosomal resistance mechanism.

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Multidrug-Resistant Transport Proteins in Yeast: Complete Inventory and Phylogenetic Characterization of Yeast Open Reading Frames within the Major Facilitator Superfamily

Cited by 137 publications

References 44 publications

The Saccharomyces cerevisiae ACR3 Gene Encodes a Putative Membrane Protein Involved in Arsenite Transport

The Saccharomyces cerevisiae ACR3 Gene Encodes a Putative Membrane Protein Involved in Arsenite Transport

Zinc Cluster Protein Rdr1p Is a Transcriptional Repressor of the PDR5 Gene Encoding a Multidrug Transporter

The SCR1 gene from Schwanniomyces occidentalis encodes a highly hydrophobic polypeptide, which confers ribosomal resistance to cycloheximide

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