{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T14:12:26Z","timestamp":1791295946771,"version":"4.1.0"},"reference-count":34,"publisher":"American Society for Microbiology","issue":"10","license":[{"start":{"date-parts":[[2012,10,1]],"date-time":"2012-10-01T00:00:00Z","timestamp":1349049600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Eukaryot Cell"],"published-print":{"date-parts":[[2012,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    In\n                    <jats:named-content content-type=\"genus-species\">Candida albicans<\/jats:named-content>\n                    , Upc2 is a zinc-cluster transcription factor that targets genes, including those of the ergosterol biosynthesis pathway. To date, three documented\n                    <jats:italic>UPC2<\/jats:italic>\n                    gain-of-function (GOF) mutations have been recovered from fluconazole-resistant clinical isolates that contribute to an increase in\n                    <jats:italic>ERG11<\/jats:italic>\n                    expression and decreased fluconazole susceptibility. In a group of 63 isolates with reduced susceptibility to fluconazole, we found that 47 overexpressed\n                    <jats:italic>ERG11<\/jats:italic>\n                    by at least 2-fold over the average expression levels in 3 unrelated fluconazole-susceptible strains. Of those 47 isolates, 29 contained a mutation in\n                    <jats:italic>UPC2<\/jats:italic>\n                    , whereas the remaining 18 isolates did not. Among the isolates containing mutations in\n                    <jats:italic>UPC2<\/jats:italic>\n                    , we recovered eight distinct mutations resulting in putative single amino acid substitutions: G648D, G648S, A643T, A643V, Y642F, G304R, A646V, and W478C. Seven of these resulted in increased\n                    <jats:italic>ERG11<\/jats:italic>\n                    expression, increased cellular ergosterol, and decreased susceptibility to fluconazole compared to the results for the wild-type strain. Genome-wide transcriptional analysis was performed for the four strongest Upc2 amino acid substitutions (A643V, G648D, G648S, and Y642F). Genes commonly upregulated by all four mutations included those involved in ergosterol biosynthesis, in oxidoreductase activity, the major facilitator efflux pump encoded by the\n                    <jats:italic>MDR1<\/jats:italic>\n                    gene, and the uncharacterized ATP binding cassette transporter\n                    <jats:italic>CDR11<\/jats:italic>\n                    . These findings demonstrate that gain-of-function mutations in\n                    <jats:italic>UPC2<\/jats:italic>\n                    are more prevalent among clinical isolates than previously thought and make a significant contribution to azole antifungal resistance, but the findings do not account for\n                    <jats:italic>ERG11<\/jats:italic>\n                    overexpression in all such isolates of\n                    <jats:named-content content-type=\"genus-species\">C. albicans<\/jats:named-content>\n                    .\n                  <\/jats:p>","DOI":"10.1128\/ec.00215-12","type":"journal-article","created":{"date-parts":[[2012,8,24]],"date-time":"2012-08-24T23:44:47Z","timestamp":1345851887000},"page":"1289-1299","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":234,"title":["Gain-of-Function Mutations in\n                    <i>UPC2<\/i>\n                    Are a Frequent Cause of\n                    <i>ERG11<\/i>\n                    Upregulation in Azole-Resistant Clinical Isolates of Candida albicans"],"prefix":"10.1128","volume":"11","author":[{"given":"Stephanie A.","family":"Flowers","sequence":"first","affiliation":[{"name":"Department of Clinical Pharmacy, University of Tennessee Health Sciences Center, Memphis, Tennessee, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine S.","family":"Barker","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy, University of Tennessee Health Sciences Center, Memphis, Tennessee, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth L.","family":"Berkow","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy, University of Tennessee Health Sciences Center, Memphis, Tennessee, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geoffrey","family":"Toner","sequence":"additional","affiliation":[{"name":"Femeris Women's Health Research Center, Medical Diagnostic Laboratories, LLC, Hamilton, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sean G.","family":"Chadwick","sequence":"additional","affiliation":[{"name":"Femeris Women's Health Research Center, Medical Diagnostic Laboratories, LLC, Hamilton, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott E.","family":"Gygax","sequence":"additional","affiliation":[{"name":"Femeris Women's Health Research Center, Medical Diagnostic Laboratories, LLC, Hamilton, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joachim","family":"Morschh\u00e4user","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Molekulare Infektionsbiologie, Universit\u00e4t W\u00fcrzburg, W\u00fcrzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P. David","family":"Rogers","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy, University of Tennessee Health Sciences Center, Memphis, Tennessee, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","volume-title":"Reference method for broth dilution antifungal susceptibility testing of yeasts; approved method M27-A3.","author":"Clinical and Laboratory Standards Institute","year":"2008","unstructured":"Clinical and Laboratory Standards Institute. 2008. Reference method for broth dilution antifungal susceptibility testing of yeasts; approved method M27-A3. Clinical and Laboratory Standards Institute, Wayne, PA."},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1534\/genetics.105.054767"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1128\/EC.3.6.1639-1652.2004"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1128\/JB.180.16.4177-4183.1998"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1534\/genetics.106.059964"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2958.2008.06309.x"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1128\/EC.00103-08"},{"key":"e_1_3_3_9_2","unstructured":"Reference deleted."},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1097\/00002030-199105000-00007"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1439-0507.1999.00498.x"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01102-09"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00995-10"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM198408093110602"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(02)08162-X"},{"key":"e_1_3_3_16_2","unstructured":"Reference deleted."},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.emboj.7600336"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.42.11.2932"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1128\/MMBR.00015-06"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.49.5.1745-1752.2005"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.fgb.2008.07.004"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0925-4439(02)00087-X"},{"key":"e_1_3_3_23_2","doi-asserted-by":"crossref","unstructured":"MorschhauserJ. 2007. 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