Loss of the yeast transporter Agp2 upregulates the pleiotropic drug-resistant pump Pdr5 and confers resistance to the protein synthesis inhibitor cycloheximide
<p dir="ltr">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 sh...
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| مؤلفون آخرون: | , , , , , , , , |
| منشور في: |
2024
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| _version_ | 1864513510668500992 |
|---|---|
| author | Yusra Manzoor (18599180) |
| author2 | Mustapha Aouida (417652) Ramya Ramadoss (16003318) Balasubramanian Moovarkumudalvan (18300811) Nisar Ahmed (584617) Abdallah Alhaj Sulaiman (17777421) Ashima Mohanty (18599183) Reem Ali (9913494) Borbala Mifsud (3907267) Dindial Ramotar (208416) |
| author2_role | author author author author author author author author author |
| author_facet | Yusra Manzoor (18599180) Mustapha Aouida (417652) Ramya Ramadoss (16003318) Balasubramanian Moovarkumudalvan (18300811) Nisar Ahmed (584617) Abdallah Alhaj Sulaiman (17777421) Ashima Mohanty (18599183) Reem Ali (9913494) Borbala Mifsud (3907267) Dindial Ramotar (208416) |
| author_role | author |
| dc.creator.none.fl_str_mv | Yusra Manzoor (18599180) Mustapha Aouida (417652) Ramya Ramadoss (16003318) Balasubramanian Moovarkumudalvan (18300811) Nisar Ahmed (584617) Abdallah Alhaj Sulaiman (17777421) Ashima Mohanty (18599183) Reem Ali (9913494) Borbala Mifsud (3907267) Dindial Ramotar (208416) |
| dc.date.none.fl_str_mv | 2024-05-22T09:00:00Z |
| dc.identifier.none.fl_str_mv | 10.1371/journal.pone.0303747 |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/journal_contribution/Loss_of_the_yeast_transporter_Agp2_upregulates_the_pleiotropic_drug-resistant_pump_Pdr5_and_confers_resistance_to_the_protein_synthesis_inhibitor_cycloheximide/26325034 |
| dc.rights.none.fl_str_mv | CC BY 4.0 info:eu-repo/semantics/openAccess |
| dc.subject.none.fl_str_mv | Biological sciences Biochemistry and cell biology Genetics Biomedical and clinical sciences Medical biochemistry and metabolomics Mitochondria Gene expression Membrane proteins Protein expression Cell membranes Yeast Saccharomyces cerevisiae RNA analysis |
| dc.title.none.fl_str_mv | Loss of the yeast transporter Agp2 upregulates the pleiotropic drug-resistant pump Pdr5 and confers resistance to the protein synthesis inhibitor cycloheximide |
| dc.type.none.fl_str_mv | Text Journal contribution info:eu-repo/semantics/publishedVersion text contribution to journal |
| description | <p dir="ltr">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 de <i>novo</i> 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<i> </i>agp2Δ 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 <i>agp2Δ</i> mutant. Moreover, a global gene expression analysis revealed that 322 genes were differentially affected in the <i>agp2Δ</i> mutant versus the parent, including the prominent <i>PDR5</i> gene and genes required for mitochondrial function. We further show that <i>Agp2</i> is associated with the upstream region of the<i> PDR5</i> gene, leading to the hypothesis that cycloheximide resistance displayed by the <i>agp2Δ</i> mutant is due to the derepression of the <i>PDR5</i> gene.</p><h2>Other Information</h2><p dir="ltr">Published in: PLOS ONE<br>License: <a href="http://creativecommons.org/licenses/by/4.0/" target="_blank">http://creativecommons.org/licenses/by/4.0/</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1371/journal.pone.0303747" target="_blank">https://dx.doi.org/10.1371/journal.pone.0303747</a></p> |
| eu_rights_str_mv | openAccess |
| id | Manara2_a88e72d616a209b26e516b2dbf8a44db |
| identifier_str_mv | 10.1371/journal.pone.0303747 |
| network_acronym_str | Manara2 |
| network_name_str | Manara2 |
| oai_identifier_str | oai:figshare.com:article/26325034 |
| publishDate | 2024 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY 4.0 |
| spelling | Loss of the yeast transporter Agp2 upregulates the pleiotropic drug-resistant pump Pdr5 and confers resistance to the protein synthesis inhibitor cycloheximideYusra Manzoor (18599180)Mustapha Aouida (417652)Ramya Ramadoss (16003318)Balasubramanian Moovarkumudalvan (18300811)Nisar Ahmed (584617)Abdallah Alhaj Sulaiman (17777421)Ashima Mohanty (18599183)Reem Ali (9913494)Borbala Mifsud (3907267)Dindial Ramotar (208416)Biological sciencesBiochemistry and cell biologyGeneticsBiomedical and clinical sciencesMedical biochemistry and metabolomicsMitochondriaGene expressionMembrane proteinsProtein expressionCell membranesYeastSaccharomyces cerevisiaeRNA analysis<p dir="ltr">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 de <i>novo</i> 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<i> </i>agp2Δ 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 <i>agp2Δ</i> mutant. Moreover, a global gene expression analysis revealed that 322 genes were differentially affected in the <i>agp2Δ</i> mutant versus the parent, including the prominent <i>PDR5</i> gene and genes required for mitochondrial function. We further show that <i>Agp2</i> is associated with the upstream region of the<i> PDR5</i> gene, leading to the hypothesis that cycloheximide resistance displayed by the <i>agp2Δ</i> mutant is due to the derepression of the <i>PDR5</i> gene.</p><h2>Other Information</h2><p dir="ltr">Published in: PLOS ONE<br>License: <a href="http://creativecommons.org/licenses/by/4.0/" target="_blank">http://creativecommons.org/licenses/by/4.0/</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1371/journal.pone.0303747" target="_blank">https://dx.doi.org/10.1371/journal.pone.0303747</a></p>2024-05-22T09:00:00ZTextJournal contributioninfo:eu-repo/semantics/publishedVersiontextcontribution to journal10.1371/journal.pone.0303747https://figshare.com/articles/journal_contribution/Loss_of_the_yeast_transporter_Agp2_upregulates_the_pleiotropic_drug-resistant_pump_Pdr5_and_confers_resistance_to_the_protein_synthesis_inhibitor_cycloheximide/26325034CC BY 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/263250342024-05-22T09:00:00Z |
| spellingShingle | Loss of the yeast transporter Agp2 upregulates the pleiotropic drug-resistant pump Pdr5 and confers resistance to the protein synthesis inhibitor cycloheximide Yusra Manzoor (18599180) Biological sciences Biochemistry and cell biology Genetics Biomedical and clinical sciences Medical biochemistry and metabolomics Mitochondria Gene expression Membrane proteins Protein expression Cell membranes Yeast Saccharomyces cerevisiae RNA analysis |
| status_str | publishedVersion |
| title | Loss of the yeast transporter Agp2 upregulates the pleiotropic drug-resistant pump Pdr5 and confers resistance to the protein synthesis inhibitor cycloheximide |
| title_full | Loss of the yeast transporter Agp2 upregulates the pleiotropic drug-resistant pump Pdr5 and confers resistance to the protein synthesis inhibitor cycloheximide |
| title_fullStr | Loss of the yeast transporter Agp2 upregulates the pleiotropic drug-resistant pump Pdr5 and confers resistance to the protein synthesis inhibitor cycloheximide |
| title_full_unstemmed | Loss of the yeast transporter Agp2 upregulates the pleiotropic drug-resistant pump Pdr5 and confers resistance to the protein synthesis inhibitor cycloheximide |
| title_short | Loss of the yeast transporter Agp2 upregulates the pleiotropic drug-resistant pump Pdr5 and confers resistance to the protein synthesis inhibitor cycloheximide |
| title_sort | Loss of the yeast transporter Agp2 upregulates the pleiotropic drug-resistant pump Pdr5 and confers resistance to the protein synthesis inhibitor cycloheximide |
| topic | Biological sciences Biochemistry and cell biology Genetics Biomedical and clinical sciences Medical biochemistry and metabolomics Mitochondria Gene expression Membrane proteins Protein expression Cell membranes Yeast Saccharomyces cerevisiae RNA analysis |