Regulation of pleiotropic drug resistance in yeast

Kołaczkowska, Anna; Goffeau, André

doi:10.1054/drup.1999.0113

Cited by 123 publications

(116 citation statements)

References 86 publications

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“…The socalled MHR is found in a large subset of the family but not War1 (43). Notably, mutations within this putative MHR cause hyperactivity of Leu3 and Pdr1/Pdr3 (16,42,44). Likewise, our data demonstrate that loss of the central region leads to constitutive War1 activity.…”

Section: Conserved Internal Domains Have Inhibitory Functions-mentioning

confidence: 57%

Weak Organic Acids Trigger Conformational Changes of the Yeast Transcription Factor War1 in Vivo to Elicit Stress Adaptation

Gregori

Schüller

Frohner

et al. 2008

Journal of Biological Chemistry

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The Saccharomyces cerevisiae zinc cluster regulator War1 mediates an essential transcriptional and adaptive response to weak organic acid stress. Here we investigate the mechanism of War1 activation upon weak acid stress. We identified several gain-of-function WAR1 alleles mapping to the central War1 region. These mutations constitutively increase levels of the plasma membrane ABC transporter Pdr12, the main War1 target mediating stress adaptation. Functional analysis of War1 reveals that the central region and its C-terminal activation domain are required for function. Notably, the native DNAbinding and dimerization domains appear dispensable for War1 activity, because they can be replaced by a LexA DNA-binding domain. Chromatin immunoprecipitation demonstrates elevated promoter affinity of activated War1, because its PDR12 promoter association increases upon stress. Hyperactive WAR1 alleles have constitutively high PDR12 promoter association. Furthermore, fluorescence resonance energy transfer of functional CFP-War1-YFP proteins also demonstrates conformational changes of stress-activated War1 in vivo. Our results suggest a mechanism whereby War1 activation is accompanied by conformational changes enhancing promoter association, thus initiating the adaptation process.Weak organic acids, such as potassium sorbate, calcium propionate, and sodium benzoate, are commonly used to preserve foods and beverages (1). In Saccharomyces cerevisiae, uncharged weak acids diffuse across the plasma membrane and dissociate inside the cell, causing intracellular acidification, free radical production, and oxidative stress (1), as well as inhibition of several metabolic processes (2). The yeast ABC transporter Pdr12 confers resistance to monocarboxylic acids with chain lengths up to C 7 (3, 4). Only organic acids but not other stresses cause a dramatic induction of PDR12 transcription and a concomitant increase of Pdr12 (4, 5). A physiological role of Pdr12 is suggested from its proposed ability to extrude amino acid catabolism by-products (6). Weak acid regulation of PDR12 occurs at the level of transcription and requires the Zn(II) 2 Cys 6 zinc cluster transcription factor War1, which recognizes and binds response elements within the PDR12 promoter (7). War1 is functionally conserved among several yeast species, including fungal pathogens. An orthologue mediating sorbate tolerance was identified in the distantly related human fungal pathogen Candida albicans (8), but the mechanism by which weak organic acids cause War1 activation is currently an open question.In S. cerevisiae, some 55 members of the binuclear zinc cluster regulator family exist (for a review see Ref. 9). Most exhibit a similar molecular architecture and domain organization. The N-terminal DNA-binding domain is followed by a coiled-coil dimerization domain, by an extended region of limited homology referred to as the "middle homology region" (MHR), 3 and finally by a short acidic stretch encompassing the C-terminal activation domain (10). Fungal zinc cluster pro...

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Section: Conserved Internal Domains Have Inhibitory Functions-mentioning

confidence: 57%

Weak Organic Acids Trigger Conformational Changes of the Yeast Transcription Factor War1 in Vivo to Elicit Stress Adaptation

Gregori

Schüller

Frohner

et al. 2008

Journal of Biological Chemistry

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“…Mutation in a few key transcription factors can directly regulate the expression of many genes. In S. cerevisiae, numerous determinants of both oxidative stress response and multidrug resistance are regulated by a complex interplay between the YAP and PDR networks of genes (27), including homologues of eight genes modulated in our experimental populations ( Table 2). Suites of genes may have been co-regulated with the resistance determinant MDR1.…”

Section: Discussionmentioning

confidence: 99%

“…In our experimental populations, CAP1 was not significantly altered in expression and no mutations were detected in the DNA sequence (data not shown). In both yeasts, the interactions in the transcriptional networks regulating multidrug transporters have yet to be experimentally dissected (27,29). In addition to transcriptional coregulation, adaptive mutations could have indirect pleiotropic effects (30) on the expression of suites of genes through interactions among various gene products (8), signaling activity across different pathways (31), or changes in cell physiology (17).…”

Section: Discussionmentioning

confidence: 99%

Population genomics of drug resistance in Candida albicans

Cowen

Nantel

Whiteway

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

129

100

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“…eliminate hundreds of structurally and functionally unrelated cytotoxic compounds, as well as potentially toxic metabolites [85]. Furthermore, Ycf1p and Bpt1p drive vacuolar sequestration of heavy metals as well as GS-conjugates [26][27][28][29]39].…”

Section: The Physiological Role Of Abc Proteins In S Cerevisiaementioning

confidence: 99%

Yeast ABC transporters – A tale of sex, stress, drugs and aging

2005

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Yeast ATP-binding cassette (ABC) proteins are implicated in many biological phenomena, often acting at crossroads of vital cellular processes. Their functions encompass peptide pheromone secretion, regulation of mitochondrial function, vacuolar detoxification, as well as pleiotropic drug resistance and stress adaptation. Because yeast harbors several homologues of mammalian ABC proteins with medical importance, understanding their molecular mechanisms, substrate interaction and three-dimensional structure of yeast ABC proteins might help identifying new approaches aimed at combating drug resistance or other ABC-mediated diseases. This review provides a comprehensive discussion on the functions of the ABC protein family in the yeast Saccharomyces cerevisiae.

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Regulation of pleiotropic drug resistance in yeast

Cited by 123 publications

References 86 publications

Weak Organic Acids Trigger Conformational Changes of the Yeast Transcription Factor War1 in Vivo to Elicit Stress Adaptation

Weak Organic Acids Trigger Conformational Changes of the Yeast Transcription Factor War1 in Vivo to Elicit Stress Adaptation

Population genomics of drug resistance in Candida albicans

Yeast ABC transporters – A tale of sex, stress, drugs and aging

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