Publication Date:
2008-04-04
Description:
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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Thakur, Jitendra K -- Arthanari, Haribabu -- Yang, Fajun -- Pan, Shih-Jung -- Fan, Xiaochun -- Breger, Julia -- Frueh, Dominique P -- Gulshan, Kailash -- Li, Darrick K -- Mylonakis, Eleftherios -- Struhl, Kevin -- Moye-Rowley, W Scott -- Cormack, Brendan P -- Wagner, Gerhard -- Naar, Anders M -- A1046223/PHS HHS/ -- CA127990/CA/NCI NIH HHS/ -- EB2026/EB/NIBIB NIH HHS/ -- GM071449/GM/NIGMS NIH HHS/ -- GM30186/GM/NIGMS NIH HHS/ -- GM47467/GM/NIGMS NIH HHS/ -- GM49825/GM/NIGMS NIH HHS/ -- R01 CA127990/CA/NCI NIH HHS/ -- England -- Nature. 2008 Apr 3;452(7187):604-9. doi: 10.1038/nature06836.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts 02129, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18385733" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Antifungal Agents/metabolism/pharmacology
;
Candida glabrata/drug effects/genetics/*metabolism
;
DNA-Binding Proteins/chemistry/genetics/metabolism
;
*Drug Resistance, Fungal/genetics
;
Fungal Proteins/chemistry/genetics/*metabolism
;
*Gene Expression Regulation, Fungal/genetics
;
Genes, Fungal/genetics
;
Mediator Complex
;
Multigene Family
;
Protein Structure, Tertiary
;
Receptors, Steroid/*metabolism
;
Saccharomyces cerevisiae/drug effects/genetics/*metabolism
;
Saccharomyces cerevisiae Proteins/chemistry/genetics/metabolism
;
Trans-Activators/chemistry/genetics/metabolism
;
Transcription Factors/metabolism
;
Transcription, Genetic/genetics
;
Xenobiotics/metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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