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Cited by 53Fungal and yeast genetics researchAntifungal resistance and susceptibilityFungal Infections and Studies

cis -Acting Elements within the Candida albicans ERG11 Promoter Mediate the Azole Response through Transcription Factor Upc2p

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Oliver, Brian G., Song, Jia L., Choiniere, Jake H., White, Theodore C.·2007·Eukaryotic Cell
DOI 10.1128/ec.00331-06PMC PMC2168239
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Abstract

The azole antifungal drugs are used to treat infections caused by Candida albicans and other fungi. These drugs interfere with the biosynthesis of ergosterol, the major sterol in fungal cells, by inhibiting an ergosterol biosynthetic enzyme, lanosterol 14 alpha-demethylase, encoded by the ERG11 gene. In vitro, these drugs as well as other ergosterol biosynthesis inhibitors increase ERG11 mRNA expression by activation of the ERG11 promoter. The signal for this activation most likely is the depletion of ergosterol, the end product of the pathway. To identify cis-acting regulatory elements that mediate this activation, ERG11 promoter fragments have been fused to the luciferase reporter gene from Renilla reniformis. Promoter deletions and linker scan mutations localized the region important for azole induction to a segment from bp -224 to -251 upstream of the start codon, specifically two 7-bp sequences separated by 13 bp. These sequences form an imperfect inverted repeat. The region is recognized by the transcription factor Upc2p and functions as an enhancer of transcription, as it can be placed upstream of a heterologous promoter in either direction, resulting in the azole induction of that promoter. The promoter constructs are not azole inducible in the upc2/upc2 homozygous deletion, demonstrating that Upc2p controls the azole induction of ERG11. These results identify an azole-responsive enhancer element (ARE) in the ERG11 promoter that is controlled by the Upc2p transcription factor. No other ARE is present in the promoter. Thus, this ARE and Upc2p are necessary and sufficient for azole induction of ERG11.

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  • Increased activity or level of the enzymes of the ergosterol pathway (e.g., ERG11) reduces direct impact of the drug on its target.

    “First, increased activity or level of the enzymes of the ergosterol pathway (e.g., ERG11) reduces direct impact of the drug on its target (Asai et al., 1999; Oliver et al., 2007).”

    From The evolution of drug resistance in clinical isolates of Candida albicans. (2015) · cites this paper as Oliver et al., 2007

  • Previously identified mechanisms of fluconazole resistance are gain-of-function, resulting in increase in amount or activity level of Erg11 or efflux of drug transporters.

    “whereas the previously identified mechanisms of fluconazole resistance are ‘gain of function’, resulting in the increase in the amount or activity level of Erg11 (Asai et al., 1999; Oliver et al., 2007) or the efflux of drug transporters (Coste et al., 2006; Dunkel et al., 2008).”

    From The evolution of drug resistance in clinical isolates of Candida albicans. (2015) · cites this paper as Oliver et al., 2007

  • LOH in several genes important for fluconazole resistance has been reported previously for ERG11, TAC1, and MRR1.

    “LOH in several genes important for fluconazole resistance has been reported previously for ERG11 (Oliver et al., 2007), TAC1 (Coste et al., 2006), and MRR1 (Schubert et al., 2011)”

    From The evolution of drug resistance in clinical isolates of Candida albicans. (2015) · cites this paper as Oliver et al., 2007

  • Two 7 bp inverted-repeat sequences located −231 and −251 bp upstream of the start codon form an azole-responsive element (ARE) regulated by Upc2, and this ARE is sufficient to induce ERG11 expression.

    “Furthermore, investigation of the ERG11 promoter through deletion and linker scan mutations concluded that two 7 bp inverted-repeat sequences located −231 and −251 bp upstream of the start codon form an azole-responsive element (ARE) regulated by Upc2 and that this ARE was sufficient to induce ERG11 expression.108”

    From Molecular and genetic basis of azole antifungal resistance in the opportunistic pathogenic fungus<i>Candida albicans</i> (2020) · cites this paper as [108]

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Authors
Oliver, B. G., Song, J. L., Choiniere, J. H., & White, T. C.
Affiliations
Center for Infectious Disease Research (US)
ORCID
Venue
Eukaryotic Cell
Publisher
American Society for Microbiology
Published
2007-12
Volume
6
Issue
12
Pages
2231-2239
ISSN
  • 1535-9778 (ISSN-L)
  • 1535-9786
DOI
10.1128/ec.00331-06
PMC
PMC2168239
OpenAlex
W2147739065
Cited by
53
References
39
Citations by year
2026: 1 · 2025: 1 · 2024: 1 · 2023: 3 · 2022: 1 · 2021: 1 · 2020: 1 · 2019: 4 · 2018: 1 · 2017: 2 · 2016: 1 · 2015: 5 · 2014: 8 · 2013: 2 · 2012: 1
FWCI
2.12
Type
journal article
Language
en
Open access
Licence
journals.asm.org/non-commercial-tdm-license (tdm)
Locations
  • Eukaryotic Cell (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health
  • National Institute of Allergy and Infectious Diseases (T32AI007509, T32-AI07509)
  • National Institute of Dental and Craniofacial Research (R01DE011367, R01 DE-11367, R01 DE 14161, R01DE014161)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
  • Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
  • Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
Keywords
Candida albicans, azole antifungals, cis-regulatory elements, ergosterol biosynthesis, lanosterol 14α-demethylase, transcriptional activation, promoter enhancer
MeSH terms
Antifungal Agents, Antigens, Fungal, Azoles, Candida albicans, Codon, Cytochrome P-450 Enzyme System, Homozygote, Luciferases, Models, Biological, Mutation, Promoter Regions, Genetic, Regulatory Sequences, Nucleic Acid, Trans-Activators, Gene Expression Regulation, Fungal, Drug Resistance, Fungal, Saccharomyces cerevisiae Proteins

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