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Acetylation of lysine 109 modulates pregnane X receptor DNA binding and transcriptional activity
D. Pasquel, A. Doricakova, H. Li, S. Kortagere, MD. Krasowski, A. Biswas, WG. Walton, MR. Redinbo, Z. Dvorak, S. Mani,
Language English Country Netherlands
Document type Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't
Links
PubMed
26855179
DOI
10.1016/j.bbagrm.2016.01.006
Knihovny.cz E-resources
- MeSH
- Acetylation MeSH
- Transcriptional Activation * MeSH
- Hep G2 Cells MeSH
- DNA chemistry metabolism MeSH
- Escherichia coli genetics metabolism MeSH
- HEK293 Cells MeSH
- HeLa Cells MeSH
- Cloning, Molecular MeSH
- Humans MeSH
- Luciferases genetics metabolism MeSH
- Lysine chemistry metabolism MeSH
- Models, Molecular MeSH
- Protein Multimerization MeSH
- Mutagenesis, Site-Directed MeSH
- Protein Processing, Post-Translational * MeSH
- Recombinant Proteins chemistry genetics metabolism MeSH
- Genes, Reporter MeSH
- Response Elements MeSH
- Protein Structure, Secondary MeSH
- Sirtuin 1 genetics metabolism MeSH
- Receptors, Steroid chemistry genetics metabolism MeSH
- Structural Homology, Protein MeSH
- p300-CBP Transcription Factors genetics metabolism MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Research Support, N.I.H., Extramural MeSH
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. This article is part of a Special Issue entitled: Xenobiotic nuclear receptors: New Tricks for An Old Dog, edited by Dr. Wen Xie.
Department of Chemistry University of North Carolina Chapel Hill NC 27599 USA
Department of Genetics Albert Einstein College of Medicine Bronx NY 10461 USA
Department of Medicine Albert Einstein College of Medicine Bronx NY 10461 USA
Department of Microbiology Raidighi College West Bengal India
Department of Pathology University of Iowa Hospitals and Clinics Iowa City IA 52242 USA
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- $a 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. This article is part of a Special Issue entitled: Xenobiotic nuclear receptors: New Tricks for An Old Dog, edited by Dr. Wen Xie.
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