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| Status |
Public on Jul 01, 2011 |
| Title |
Regulation of efflux pump expression and drug resistance by the transcription factors Mrr1, Upc2, and Cap1 in Candida albicans |
| Organism |
Candida albicans |
| Experiment type |
Expression profiling by array
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| Summary |
Constitutive overexpression of the Mdr1 efflux pump is an important mechanism of acquired drug resistance in the yeast Candida albicans. The zinc cluster transcription factor Mrr1 is a central regulator of MDR1 expression, but other transcription factors have also been implicated in MDR1 regulation. To better understand how MDR1-mediated drug resistance is achieved in this important fungal pathogen, we studied the interdependence of Mrr1 and two other MDR1 regulators, Upc2 and Cap1, in the control of MDR1 expression. A mutated, constitutively active Mrr1 could upregulate MDR1 and confer drug resistance in the absence of Upc2 or Cap1. On the other hand, Upc2 containing a gain-of-function mutation only slightly activated the MDR1 promoter, and this activation depended on the presence of a functional MRR1 gene. In contrast, a C-terminally truncated, activated form of Cap1 could upregulate MDR1 in a partially Mrr1-independent fashion. The induction of MDR1 expression by toxic chemicals occurred independently of Upc2, but required the presence of Mrr1 and also partially depended on Cap1. Transcriptional profiling and in vivo DNA binding studies showed that a constitutively active Mrr1 binds to and upregulates most of its direct target genes in the presence or absence of Cap1. Therefore, Mrr1 and Cap1 cooperate in the environmental induction of MDR1 expression in wild-type C. albicans, but gain-of-function mutations in either of the two transcription factors can independently mediate efflux pump overexpression and drug resistance.
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| Overall design |
We endeavored to determine how the function of a gain-of-function allele of MRR1 (shown to confer high-level azole resistance) is affected when the CAP1 gene is disrupted.
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| Contributor(s) |
Schubert S, Barker KS, Znaidi S, Schneider S, Dierolf F, Dunkel N, Aid M, Boucher G, Rogers PD, Raymond M, Morschhauser J |
| Citation(s) |
21402859 |
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| Submission date |
Aug 10, 2010 |
| Last update date |
Sep 21, 2012 |
| Contact name |
Katherine S Barker |
| E-mail(s) |
[email protected]
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| Organization name |
University of Tennessee Health Science Center
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| Department |
Clinical Pharmacy
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| Lab |
David Rogers laboratory
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| Street address |
881 Madison Avenue, Room 305
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| City |
Memphis |
| State/province |
TN |
| ZIP/Postal code |
38163 |
| Country |
USA |
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| Platforms (1) |
| GPL6808 |
[CAN07a520619F] Candida albicans 11-mer Affymetrix 10K array version1 |
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| Samples (7)
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| Relations |
| BioProject |
PRJNA131763 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE23532_RAW.tar |
9.2 Mb |
(http)(custom) |
TAR (of CEL, CHP) |
| Processed data included within Sample table |
| Processed data provided as supplementary file |
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