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Accepted (AM)Open Access (License Unspecified), Open
Journal article
Acetylation of lysine 109 modulates pregnane X receptor DNA binding and transcriptional activity
Biochimica et biophysica acta, v 1859(9), pp 1155-1169
23 Feb 2016
PMID: 26855179
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Pregnane X receptor (PXR) is a major transcriptional regulator of
xenobiotic metabolism and transport pathways in the liver and intestines, which
are critical for protecting organisms against potentially harmful xenobiotic and
endobiotic compounds. Inadvertent activation of drug metabolism pathways through
PXR is known to contribute to drug resistance, adverse drug–drug
interactions, and drug toxicity in humans. In both humans and rodents, PXR has
been implicated in non-alcoholic fatty liver disease, diabetes, obesity,
inflammatory bowel disease, and cancer. Because of PXR's important
functions, it has been a therapeutic target of interest for a long time. More
recent mechanistic studies have shown that PXR is modulated by multiple PTMs.
Herein we provide the first investigation of the role of acetylation in
modulating PXR activity. Through LC–MS/MS analysis, we identified lysine
109 (K109) in the hinge as PXR's major acetylation site. Using various
biochemical and cell-based assays, we show that PXR's acetylation status
and transcriptional activity are modulated by E1A binding protein (p300) and
sirtuin 1 (SIRT1). Based on analysis of acetylation site mutants, we found that
acetylation at K109 represses PXR transcriptional activity. The mechanism
involves loss of RXRα dimerization and reduced binding to cognate DNA
response elements. This mechanism may represent a promising therapeutic target
using modulators of PXR acetylation levels.
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Details
- Title
- Acetylation of lysine 109 modulates pregnane X receptor DNA binding and transcriptional activity
- Creators
- Danielle Pasquel - Albert Einstein College of MedicineAneta Doricakova - Palacký University, OlomoucHao Li - Albert Einstein College of MedicineSandhya Kortagere - Drexel UniversityMatthew D. Krasowski - University of Iowa Hospitals and ClinicsArunima Biswas - Department of Microbiology, Raidighi College, West Bengal, India.William G. Walton - University of North Carolina at Chapel HillMatthew R. Redinbo - University of North Carolina at Chapel HillZdenek Dvorak - Palacký University, OlomoucSridhar Mani - Albert Einstein College of Medicine
- Publication Details
- Biochimica et biophysica acta, v 1859(9), pp 1155-1169
- Publisher
- Elsevier
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology
- Web of Science ID
- WOS:000381952100009
- Scopus ID
- 2-s2.0-84959157340
- Other Identifier
- 991019167797804721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology
- Biophysics