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Molecular Pharmacology

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Research ArticleArticle

Dual Roles for Splice Variants of the Glucuronidation Pathway as Regulators of Cellular Metabolism

Mélanie Rouleau, Joannie Roberge, Judith Bellemare and Chantal Guillemette
Molecular Pharmacology January 2014, 85 (1) 29-36; DOI: https://doi.org/10.1124/mol.113.089227
Mélanie Rouleau
Pharmacogenomics Laboratory, Centre Hospitalier Universitaire de Québec Research Center, Faculty of Pharmacy, Laval University, Québec City, Québec, Canada
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Joannie Roberge
Pharmacogenomics Laboratory, Centre Hospitalier Universitaire de Québec Research Center, Faculty of Pharmacy, Laval University, Québec City, Québec, Canada
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Judith Bellemare
Pharmacogenomics Laboratory, Centre Hospitalier Universitaire de Québec Research Center, Faculty of Pharmacy, Laval University, Québec City, Québec, Canada
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Chantal Guillemette
Pharmacogenomics Laboratory, Centre Hospitalier Universitaire de Québec Research Center, Faculty of Pharmacy, Laval University, Québec City, Québec, Canada
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Abstract

Transcripts of the UGT1A gene, encoding half of human UDP-glucuronosyltransferase (UGT) enzymes, undergo alternative splicing, resulting in active enzymes named isoforms 1 (i1s) and novel truncated isoforms 2 (i2s). Here, we investigated the effects of depleting endogenous i2 on drug response and attempted to unveil any additional biologic role(s) for the truncated novel UGT proteins. We used an integrated systems biology approach that combines RNA interference with unbiased global genomic and proteomic screens, and used HT115 colorectal cancer cells as a model. Consistent with previous evidence suggesting that i2s negatively regulate i1s through protein–protein interactions, i2-depleted cells were less sensitive to drug-induced cell death (IC50 of 0.45 ± 0.05 µM versus 0.22 ± 0.03 µM; P = 0.006), demonstrating that modulation of i2 levels meaningfully impacts drug bioavailability and cellular response. We also observed reduced production of reactive oxygen species by 30% (P < 0.05), and an enhanced expression (>1.2-fold; P < 0.05) of several proteins, such as hemoglobin α genes and superoxide dismutase 1, that have network functions associated with antioxidant properties. Interaction proteomics analysis of endogenous proteins from the cellular model, mainly in human intestine but also in kidney tissues, further uncovered interactions between i2s (but not i1s) and the antioxidant enzymes catalase and peroxiredoxin 1, which may influence antioxidant potential through sequestration of these novel partners. Our findings demonstrate for the first time dual roles for i2s in the cellular defense system as endogenous regulators of drug response as well as in oxidative stress.

Footnotes

    • Received August 20, 2013.
    • Accepted October 18, 2013.
  • This research was supported by the Canadian Institutes of Health Research (CIHR) [Grant MOP-84223/111086]; the National Sciences and Engineering Research Council of Canada [Grant CG086976]; and the Canada Research Chair Program [(to C.G.)]. M.R., J.R., and J.B. received a CIHR Frederick Banting and Charles Best Canada Graduate Scholarship studentship award, and J.R. received a studentship award from the Fonds de la recherche en santé du Québec. C.G. holds a Tier II Canada Research Chair in Pharmacogenomics.

  • dx.doi.org/10.1124/mol.113.089227.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 85 (1)
Molecular Pharmacology
Vol. 85, Issue 1
1 Jan 2014
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Research ArticleArticle

Roles of UGT1A Splice Variants in Cellular Defense

Mélanie Rouleau, Joannie Roberge, Judith Bellemare and Chantal Guillemette
Molecular Pharmacology January 1, 2014, 85 (1) 29-36; DOI: https://doi.org/10.1124/mol.113.089227

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Research ArticleArticle

Roles of UGT1A Splice Variants in Cellular Defense

Mélanie Rouleau, Joannie Roberge, Judith Bellemare and Chantal Guillemette
Molecular Pharmacology January 1, 2014, 85 (1) 29-36; DOI: https://doi.org/10.1124/mol.113.089227
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