The DOI matches its Crossref record; 61 of the 62 references it cites were found in a registry or an index.
Genomewide Location Analysis of Candida albicans Upc2p, a Regulator of Sterol Metabolism and Azole Drug Resistance
Open accessAbstract
Upc2p, a transcription factor of the zinc cluster family, is an important regulator of sterol biosynthesis and azole drug resistance in Candida albicans . To better understand Upc2p function in C. albicans , we used genomewide location profiling to identify the transcriptional targets of Upc2p in vivo. A triple hemagglutinin epitope, introduced at the C terminus of Upc2p, conferred a gain-of-function effect on the fusion protein. Location profiling identified 202 bound promoters ( P < 0.05). Overrepresented functional groups of genes whose promoters were bound by Upc2p included 12 genes involved in ergosterol biosynthesis ( NCP1 , ERG11 , ERG2 , and others), 18 genes encoding ribosomal subunits ( RPS30 , RPL32 , RPL12 , and others), 3 genes encoding drug transporters ( CDR1 , MDR1 , and YOR1 ), 4 genes encoding transcription factors ( INO2 , ACE2 , SUT1 , and UPC2 ), and 6 genes involved in sulfur amino acid metabolism ( MET6 , SAM2 , SAH1 , and others). Bioinformatic analyses suggested that Upc2p binds to the DNA motif 5′-VNCGBDTR that includes the previously characterized Upc2p binding site 5′-TCGTATA. Northern blot analysis showed that increased binding correlates with increased expression for the analyzed Upc2p targets ( ERG11 , MDR1 , CDR1 , YOR1 , SUT1 , SMF12 , and CBP1 ). The analysis of ERG11 , MDR1 , and CDR1 transcripts in wild-type and upc2 Δ/ upc2 Δ strains grown under Upc2p-activating conditions (lovastatin treatment and hypoxia) showed that Upc2p regulates its targets in a complex manner, acting as an activator or as a repressor depending upon the target and the activating condition. Taken together, our results indicate that Upc2p is a key regulator of ergosterol metabolism. They also suggest that Upc2p may contribute to azole resistance by regulating the expression of drug efflux pump-encoding genes in addition to ergosterol biosynthesis genes.
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In the citing paper
“The addition of a 3 HA tag to the C-terminal domain of zinc cluster transcription factors was shown to be efficient for their artificial activation in C. albicans and C. auris, presumably by relieving an activation domain from repression by an inhibitory domain (32–35).”
From Ume6-dependent pathways of morphogenesis and biofilm formation in Candida auris (2024) · cites this paper as [35]
In the citing paper
“Interestingly, UPC2 wasnotfoundtobeupregulated in any of the four strains analyzed by microarray analysis, although Upc2 is thought to autoregulate and has been shown to bind its own promoter in experiments using chromatin immunoprecipitation with microarray technology (ChIP-chip) (33).”
From Gain-of-Function Mutations in UPC2 Are a Frequent Cause of ERG11 Upregulation in Azole-Resistant Clinical Isolates of Candida albicans (2012) · cites this paper as [33]
In the citing paper
“Upc2 has previously been shown to bind to the promoter of the drug efflux pump MDR1 but was not a cause of Mdr1-mediated drug resistance (28, 33).”
From Gain-of-Function Mutations in UPC2 Are a Frequent Cause of ERG11 Upregulation in Azole-Resistant Clinical Isolates of Candida albicans (2012) · cites this paper as [33]
In the citing paper
“However, UPC2 induction does not increase significantly with escalating FS concentrations (factor 1.69 +/− 0.24 at 20 μM) and can thus not explain an adaptive response at intermediate concentrations.”
From Inhibition of Candida albicans by Fluvastatin Is Dependent on pH (2009) · cites this paper as [10]
In the citing paper
“Induction of the major steroid synthesis regulator UPC2 [10], as determined by qPCR, is detectable at low FS concentrations (factor 1.53 +/− 0.28 at 0.5 μM), indicating that FS indeed has a physiological effect in this range.”
From Inhibition of Candida albicans by Fluvastatin Is Dependent on pH (2009) · cites this paper as [10]
In the citing paper
“If a certain level of inhibition is exceeded, the cell might respond by inducing the activity of the steroid synthesis pathway [10, 13], apparently by a UPC2-independent mechanism.”
From Inhibition of Candida albicans by Fluvastatin Is Dependent on pH (2009) · cites this paper as [10]
In the citing paper
“A ChIP-chip experiment was carried out on C. albicans Upc2 and this factor was found to associate with the CDR1 gene in this species [39].”
From The Candida glabrata Upc2A transcription factor is a global regulator of antifungal drug resistance pathways (2021) · cites this paper as [39]
In the citing paper
“Through genome-wide gene expression profiling, several ergosterol biosynthesis genes, including ERG11, were determined to be coordinately up-regulated with UPC2 in fluconazole-resistant isolates”
From Molecular and genetic basis of azole antifungal resistance in the opportunistic pathogenic fungus Candida albicans (2020) · cites this paper as [110]
In the citing paper
“and ChIP-microarray location analysis identified 202 promoters bound by Upc2, including not only ergosterol biosynthesis genes (NCP1, ERG11, ERG1, ERG2, ERG24, ERG4, ERG5, ERG6, ERG9, ERG10, ERG25, ERG251 and UPC2) but also other transcription factors and the drug transporter genes CDR1 and MDR1.109–111”
From Molecular and genetic basis of azole antifungal resistance in the opportunistic pathogenic fungus Candida albicans (2020) · cites this paper as [110]
In the citing paper
“Upc2, however, was also shown to have a regulatory role in more than just sterol biosynthesis genes.”
From Molecular and genetic basis of azole antifungal resistance in the opportunistic pathogenic fungus Candida albicans (2020) · cites this paper as [110]
Citations
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Metadata
- Authors
- Znaidi, S., Weber, S., Zin Al-Abdin, O., Bomme, P., Saidane, S., Drouin, S., Lemieux, S., De Deken, X., Robert, F., & Raymond, M.
- Affiliations
- Institute for Research in Immunology and Cancer (CA)
- Institute for Research in Immunology and Cancer, Université de Montréal, Montreal, Québec, Canada
- Université de Lille (FR)
- Université Libre de Bruxelles (BE)
- Institut de Recherches Cliniques de Montréal (affiliated with Université de Montréal), Montreal, Québec, Canada
- Corresponding author
- Raymond, Martine
- Venue
- Eukaryotic Cell
- Publisher
- American Society for Microbiology
- Published
- 2008-05
- Volume
- 7
- Issue
- 5
- Pages
- 836-847
- ISSN
- 1535-9778 (ISSN-L)
- 1535-9786
- PMC
- PMC2394978
- OpenAlex
- W2157149808
- Semantic Scholar
- 52cb6cbded8e4120b39613b447fe88c3c49585fd
- Cited by
- 119
- References
- 62
- Citations by year
- 2026: 6 · 2025: 3 · 2024: 6 · 2023: 7 · 2022: 2 · 2021: 4 · 2020: 5 · 2019: 5 · 2018: 5 · 2017: 7 · 2016: 3 · 2015: 5 · 2014: 11 · 2013: 6 · 2012: 4
- FWCI
- 5.34
- Type
- journal article
- Language
- en
- Open access
- diamond
- doi.org
- Locations
- Eukaryotic Cell (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Dépôt institutionnel de l'Université libre de Bruxelles (Université Libre de Bruxelles) (submittedVersion)
- Funders
- Canadian Institutes of Health Research (CTP79843, MT-15679)
- Natural Sciences and Engineering Research Council of Canada (312023-2005)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- Candida albicans, transcription factors, zinc cluster transcription factors, sterol metabolism, ergosterol biosynthesis, drug efflux pumps, MDR1, CDR1, promoter binding, transcriptional regulation, lovastatin, hypoxia, sulfur amino acid metabolism, ribosomal subunits
- MeSH terms
- Azoles, Binding Sites, Candida albicans, Fungal Proteins, Promoter Regions, Genetic, Recombinant Fusion Proteins, Sterols, Transcription Factors, Transcription, Genetic, Gene Expression Regulation, Fungal, Genome, Fungal, Oligonucleotide Array Sequence Analysis, Amino Acid Motifs, Gene Expression Profiling, Drug Resistance, Fungal, Chromatin Immunoprecipitation
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