Saccharomyces cerevisiae Basic Region-Leucine Zipper Protein Regulatory Networks Converge at the ATR1 Structural Gene

Coleman, Sean T.; Tseng, Edith; Moye‐Rowley, W. Scott

doi:10.1074/jbc.272.37.23224

Cited by 62 publications

(53 citation statements)

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“…Atr1, a member of the 14 spanner drug : H + antiporters DHA2 family, confers resistance to aminotriazole (Kanazawa et al, 1988), a competitive inhibitor of the HIS3 gene product, causing histidine starvation, and has been shown to be the main boron exporter in yeast (Kaya et al, 2009). Interestingly, Gcn4 also controls the expression of ATR1 through the Yap-1 recognition element (Coleman et al, 1997), and the upregulation of QDR2 (Vargas et al, 2007) and QDR3 (this work) under limitation of the nitrogen or amino acid source. Whether or not the upregulation of QDR3 in the presence of polyamine-induced stress and in nitrogen/amino acid limitation conditions is linked somehow remains to be clarified.…”

Section: Discussionmentioning

confidence: 96%

“…Although the exact mechanism underlying a possible pro-oxidant action of polyamines is still unknown, a survey on the dual role of polyamines as anti-oxidant/pro-oxidant agents has verified that these compounds do act as pro-oxidant agents in the presence of free iron (Mozdzan et al, 2006). Yap1 also plays a role in the control of MDR, regulating the expression of at least two other MFS-MDR proteins, Flr1 (Brô co et al, 1999;Tenreiro et al, 2001) and Atr1 (Coleman et al, 1997). Atr1, a member of the 14 spanner drug : H + antiporters DHA2 family, confers resistance to aminotriazole (Kanazawa et al, 1988), a competitive inhibitor of the HIS3 gene product, causing histidine starvation, and has been shown to be the main boron exporter in yeast (Kaya et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

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Yeast response and tolerance to polyamine toxicity involving the drug : H+ antiporter Qdr3 and the transcription factors Yap1 and Gcn4

et al. 2011

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The yeast QDR3 gene encodes a plasma membrane drug : H + antiporter of the DHA1 family that was described as conferring resistance against the drugs quinidine, cisplatin and bleomycin and the herbicide barban, similar to its close homologue QDR2. In this work, a new physiological role for Qdr3 in polyamine homeostasis is proposed. QDR3 is shown to confer resistance to the polyamines spermine and spermidine, but, unlike Qdr2, also a determinant of resistance to polyamines, Qdr3 has no apparent role in K + homeostasis. QDR3 transcription is upregulated in yeast cells exposed to spermine or spermidine dependent on the transcription factors Gcn4, which controls amino acid homeostasis, and Yap1, the main regulator of oxidative stress response. Yap1 was found to be a major determinant of polyamine stress resistance in yeast and is accumulated in the nucleus of yeast cells exposed to spermidine-induced stress. QDR3 transcript levels were also found to increase under nitrogen or amino acid limitation; this regulation is also dependent on Gcn4. Consistent with the concept that Qdr3 plays a role in polyamine homeostasis, QDR3 expression was found to decrease the intracellular accumulation of [ 3 H]spermidine, playing a role in the maintenance of the plasma membrane potential in spermidine-stressed cells. INTRODUCTIONMultidrug efflux transporters are found in all living cells and are thought to recognize a wide variety of structurally and pharmacologically unrelated drugs. They are proposed to actively extrude or compartmentalize drugs and other xenobiotics, thus providing protection from these compounds (Jungwirth & Kuchler, 2006;Paulsen, 2003;Prasad et al., 2002;Roepe et al., 1996;. The activity of these proteins underlies the manifestation of cellular drug resistance, seriously limiting the therapeutic potential of drugs (Hayes & Wolf, 1997). The in silico analysis of the yeast genome revealed the existence of 23 putative drug : H + antiporters of the multiple drug resistance (MDR) family of the major facilitator superfamily (MFS). Although many of these proteins have been shown to confer resistance to a wide variety of drugs and chemicals (Paulsen et al., 1998;, the molecular mechanisms behind their apparent promiscuity remain elusive and a topic of debate (Jungwirth & Kuchler, 2006;Paulsen, 2003;Prasad et al., 2002;Roepe et al., 1996;.In the present work, we have further examined the biological function of the MFS-MDR transporter encoded by the QDR3 gene, which is present in the plasma membrane of Saccharomyces cerevisiae (Huh et al., 2003;Tenreiro et al., 2005). Qdr3 belongs to cluster I of the DHA1 drug efflux family, including putative drug : H + antiporters with 12 predicted membrane-spanning segments (Paulsen et al., 1998), and confers yeast resistance against the antiarrhythmic and antimalarial drug quinidine, the herbicide barban and the antitumour agents bleomycin and cisplatin (Tenreiro et al., 2005). Through genome-wide screenings, QDR3 gene deletion was also found to increase yeast susceptibility towards ma...

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Yeast response and tolerance to polyamine toxicity involving the drug : H+ antiporter Qdr3 and the transcription factors Yap1 and Gcn4

et al. 2011

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“…ATR1 is required for yeast resistance to aminotriazole (18), a competitive inhibitor of the HIS3 gene product, an imidazoleglycerolphosphate dehydratase (20,42), causing histidine starvation. Interestingly, Gcn4p also controls the expression of ATR1 through a DNA element related to the yAP-1 recognition element (7). Also, in the case of the QDR2 promoter region, there is no established DNA binding site for Gcn4p [the sequence TGA(G/G)TCA].…”

Section: Discussionmentioning

confidence: 99%

“…Since Gcn4p was proven to compete with Sko1p for these binding sites in the HAL1 promoter region (28), it is possible that they may also be used to bind Gcn4p to the QDR2 promoter region. Moreover, there are three yAP-1 sequences in the QDR2 promoter region also recognized by Gcn4p and Yap1p (7).…”

Section: Discussionmentioning

confidence: 99%

Saccharomyces cerevisiae Multidrug Resistance Transporter Qdr2 Is Implicated in Potassium Uptake, Providing a Physiological Advantage to Quinidine-Stressed Cells

et al. 2007

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The QDR2 gene of Saccharomyces cerevisiae encodes a putative plasma membrane drug:H ؉ antiporter that confers resistance against quinidine, barban, bleomycin, and cisplatin. This work provides experimental evidence of defective K ؉ (Rb ؉ ) uptake in the absence of QDR2. The direct involvement of Qdr2p in K ؉ uptake is reinforced by the fact that increased K ؉ (Rb ؉ ) uptake due to QDR2 expression is independent of the Trk1p/Trk2p system. QDR2 expression confers a physiological advantage for the yeast cell during the onset of K ؉ limited growth, due either to a limiting level of K ؉ in the growth medium or to the presence of quinidine. This drug decreases the K ؉ uptake rate and K ؉ accumulation in the yeast cell, especially in the ⌬qdr2 mutant. Qdr2p also helps to sustain the decrease of intracellular pH in quinidine-stressed cells in growth medium at pH 5.5 by indirectly promoting H ؉ extrusion affected by the drug. The results are consistent with the hypothesis that Qdr2p may also couple K ؉ movement with substrate export, presumably with quinidine. Other clues to the biological role of QDR2 in the yeast cell come from two additional lines of experimental evidence. First, QDR2 transcription is activated under nitrogen (NH 4 ؉ ) limitation or when the auxotrophic strain examined enters stationary phase due to leucine limitation, this regulation being dependent on general amino acid control by Gcn4p. Second, the amino acid pool is higher in ⌬qdr2 cells than in wild-type cells, indicating that QDR2 expression is, directly or indirectly, involved in amino acid homeostasis.

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“…Yap1p targets involved in oxidative stress response include TRX2 (thioredoxin) (5), GSH1 (␥-glutamylcysteine synthetase) (6), GSH2 (glutathione synthetase) (7), TRR1 (thioredoxin reductase) (8), GLR1 (glutathione reductase) (9), GPX2 (glutathione peroxidase) (10), TSA1 (thioredoxin peroxidase) (10,11), and AHP1 (alkyl hydroperoxide reductase) (12). Yap1p also regulates the transcription of genes encoding membrane-associated transporters such as YCF1, coding for an ATP binding cassette (ABC) transporter, which functions as a glutathione S-conjugate pump (13), as well as ATR1 and FLR1, coding for MDR transporters of the major facilitator superfamily (14,15). Large-scale studies investigating Yap1p-dependent transcription have identified several additional genes that appear to be directly or indirectly regulated by Yap1p (11,16,17), underscoring the importance of this transcription factor in regulating stress response pathways.…”

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confidence: 99%

Multiple Yap1p-binding Sites Mediate Induction of the Yeast Major Facilitator FLR1 Gene in Response to Drugs, Oxidants, and Alkylating Agents

Nguyên

Alarco

Raymond

2001

Journal of Biological Chemistry

100

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The bZip transcription factor Yap1p plays an important role in oxidative stress response and multidrug resistance in Saccharomyces cerevisiae. We have previously demonstrated that the FLR1 gene, encoding a multidrug transporter of the major facilitator superfamily, is a transcriptional target of Yap1p. The FLR1 promoter contains three potential Yap1p response elements (YREs) at positions ؊148 (YRE1), ؊167 (YRE2), and ؊364 (YRE3). To address the function of these YREs, the three sites have been individually mutated and tested in transactivation assays. Our results show that (i) each of the three YREs is functional and important for the optimal transactivation of FLR1 by Yap1p and that (ii) the three YREs are not functionally equivalent, mutation of YRE3 being the most deleterious, followed by YRE2 and YRE1. Simultaneous mutation of the three YREs abolished transactivation of the promoter by Yap1p, demonstrating that the three sites are essential for the regulation of FLR1 by Yap1p. Gel retardation assays confirmed that Yap1p differentially binds to the three YREs (YRE3 > YRE2 > YRE1). We show that the transcription of FLR1 is induced upon cell treatment with the oxidizing agents diamide, diethylmaleate, hydrogen peroxide, and tert-butyl hydroperoxide, the antimitotic drug benomyl, and the alkylating agent methylmethane sulfonate and that this induction is mediated by Yap1p through the three YREs. 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.

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Saccharomyces cerevisiae Basic Region-Leucine Zipper Protein Regulatory Networks Converge at the ATR1 Structural Gene

Cited by 62 publications

References 49 publications

Yeast response and tolerance to polyamine toxicity involving the drug : H+ antiporter Qdr3 and the transcription factors Yap1 and Gcn4

Yeast response and tolerance to polyamine toxicity involving the drug : H+ antiporter Qdr3 and the transcription factors Yap1 and Gcn4

Saccharomyces cerevisiae Multidrug Resistance Transporter Qdr2 Is Implicated in Potassium Uptake, Providing a Physiological Advantage to Quinidine-Stressed Cells

Multiple Yap1p-binding Sites Mediate Induction of the Yeast Major Facilitator FLR1 Gene in Response to Drugs, Oxidants, and Alkylating Agents

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