{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T09:35:41Z","timestamp":1789032941661,"version":"build-2803163510"},"reference-count":66,"publisher":"Public Library of Science (PLoS)","issue":"5","license":[{"start":{"date-parts":[[2024,5,22]],"date-time":"2024-05-22T00:00:00Z","timestamp":1716336000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100007458","name":"Qatar Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007458","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>The transmembrane protein Agp2, initially shown as a transporter of L-carnitine, mediates the high-affinity transport of polyamines and the anticancer drug bleomycin-A5. Cells lacking Agp2 are hyper-resistant to polyamine and bleomycin-A5. In these earlier studies, we showed that the protein synthesis inhibitor cycloheximide blocked the uptake of bleomycin-A5 into the cells suggesting that the drug uptake system may require <jats:italic>de novo<\/jats:italic> synthesis. However, our recent findings demonstrated that cycloheximide, instead, induced rapid degradation of Agp2, and in the absence of Agp2 cells are resistant to cycloheximide. These observations raised the possibility that the degradation of Agp2 may allow the cell to alter its drug resistance network to combat the toxic effects of cycloheximide. In this study, we show that membrane extracts from <jats:italic>agp2\u0394<\/jats:italic> mutants accentuated several proteins that were differentially expressed in comparison to the parent. Mass spectrometry analysis of the membrane extracts uncovered the pleiotropic drug efflux pump, Pdr5, involved in the efflux of cycloheximide, as a key protein upregulated in the <jats:italic>agp2\u0394<\/jats:italic> mutant. Moreover, a global gene expression analysis revealed that 322 genes were differentially affected in the <jats:italic>agp2\u0394<\/jats:italic> mutant <jats:italic>versus<\/jats:italic> the parent, including the prominent <jats:italic>PDR5<\/jats:italic> gene and genes required for mitochondrial function. We further show that Agp2 is associated with the upstream region of the <jats:italic>PDR5<\/jats:italic> gene, leading to the hypothesis that cycloheximide resistance displayed by the <jats:italic>agp2\u0394<\/jats:italic> mutant is due to the derepression of the <jats:italic>PDR5<\/jats:italic> gene.<\/jats:p>","DOI":"10.1371\/journal.pone.0303747","type":"journal-article","created":{"date-parts":[[2024,5,22]],"date-time":"2024-05-22T17:33:25Z","timestamp":1716399205000},"page":"e0303747","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":2,"title":["Loss of the yeast transporter Agp2 upregulates the pleiotropic drug-resistant pump Pdr5 and confers resistance to the protein synthesis inhibitor cycloheximide"],"prefix":"10.1371","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-8997-5275","authenticated-orcid":true,"given":"Yusra","family":"Manzoor","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7945-5320","authenticated-orcid":true,"given":"Mustapha","family":"Aouida","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3144-4080","authenticated-orcid":true,"given":"Ramya","family":"Ramadoss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1140-883X","authenticated-orcid":true,"given":"Balasubramanian","family":"Moovarkumudalvan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nisar","family":"Ahmed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6720-9269","authenticated-orcid":true,"given":"Abdallah 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