Journal article
A nuclear receptor-like pathway regulating multidrug resistance in fungi
Nature (London), Vol.452(7187), pp.604-609
04/03/2008
DOI: 10.1038/nature06836
PMID: 18385733
Abstract
Multidrug resistance (MDR) is a serious complication during treatment of opportunistic fungal infections that frequently afflict immunocompromised individuals, such as transplant recipients and cancer patients undergoing cytotoxic chemotherapy. Improved knowledge of the molecular pathways controlling MDR in pathogenic fungi should facilitate the development of novel therapies to combat these intransigent infections. MDR is often caused by upregulation of drug efflux pumps by members of the fungal zinc-cluster transcription-factor family (for example Pdr1p orthologues). However, the molecular mechanisms are poorly understood. Here we show that Pdr1p family members in Saccharomyces cerevisiae and the human pathogen Candida glabrata directly bind to structurally diverse drugs and xenobiotics, resulting in stimulated expression of drug efflux pumps and induction of MDR. Notably, this is mechanistically similar to regulation of MDR in vertebrates by the PXR nuclear receptor, revealing an unexpected functional analogy of fungal and metazoan regulators of MDR. We have also uncovered a critical and specific role of the Gal11p/MED15 subunit of the Mediator co-activator and its activator-targeted KIX domain in antifungal/xenobiotic-dependent regulation of MDR. This detailed mechanistic understanding of a fungal nuclear receptor-like gene regulatory pathway provides novel therapeutic targets for the treatment of multidrug-resistant fungal infections.
Details
- Title: Subtitle
- A nuclear receptor-like pathway regulating multidrug resistance in fungi
- Creators
- Jitendra K Thakur - Massachusetts General HospitalHaribabu Arthanari - Harvard University ,Fajun Yang - Harvard University ,Shih-Jung Pan - Johns Hopkins UniversityXiaochun Fan - Harvard University ,Julia Breger - Harvard University ,Dominique P Frueh - Harvard University ,Kailash Gulshan - University of IowaDarrick K Li - Harvard University ,Eleftherios Mylonakis - Harvard University ,Kevin Struhl - Harvard University ,W Scott Moye-Rowley - University of IowaBrendan P Cormack - Department of Molecular Biology and Genetics Johns Hopkins School of Medicine Baltimore, Maryland 21205, USAGerhard Wagner - Harvard University ,Anders M Näär - Harvard University ,
- Resource Type
- Journal article
- Publication Details
- Nature (London), Vol.452(7187), pp.604-609
- DOI
- 10.1038/nature06836
- PMID
- 18385733
- ISSN
- 0028-0836
- eISSN
- 1476-4687
- Grant note
- CA127990 / NCI NIH HHS R01 CA127990 / NCI NIH HHS EB2026 / NIBIB NIH HHS GM49825 / NIGMS NIH HHS GM30186 / NIGMS NIH HHS GM071449 / NIGMS NIH HHS A1046223 / PHS HHS GM47467 / NIGMS NIH HHS
- Language
- English
- Date published
- 04/03/2008
- Academic Unit
- Molecular Physiology and Biophysics; Internal Medicine
- Record Identifier
- 9984297599402771
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