The hPXR (human pregnane X receptor), a major chemical toxin sensor, is a ligand-induced transcription factor activated by various xenobiotics and toxins, resulting in the transcriptional up-regulation of detoxifying enzymes. To date, little is known about the upstream regulation of hPXR. Using MS analysis and a kinome-wide siRNA screen, we report that the E3 ligase UBR5 (ubiquitin protein ligase E3 component n-recognin 5) and DYRK2 (dual-specificity tyrosine-phosphorylation-regulated kinase 2) regulate hPXR stability. UBR5 knockdown resulted in accumulation of cellular hPXR and a concomitant increase in hPXR activity, whereas the rescue of UBR5 knockdown decreased the cellular hPXR level and activity. Importantly, UBR5 exerted its effect in concert with the serine/threonine kinase DYRK2, as the knockdown of DYRK2 phenocopied UBR5 knockdown. hPXR was shown to be a substrate for DYRK2, and DYRK2-dependent phosphorylation of hPXR facilitated its subsequent ubiquitination by UBR5. This is the first report of the post-translational regulation of hPXR via phosphorylation-facilitated ubiquitination by DYRK2 and UBR5. The results of the present study reveal the role of the ubiquitin–proteasomal pathway in modulating hPXR activity and indicate that pharmacological inhibitors of the ubiquitin–proteasomal pathway that regulate hPXR stability may negatively affect treatment outcome from unintended hPXR-mediated drug–drug interactions.
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Research Article|
March 14 2014
Stability of the human pregnane X receptor is regulated by E3 ligase UBR5 and serine/threonine kinase DYRK2
Su Sien Ong;
Su Sien Ong
*Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, U.S.A.
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Asli N. Goktug;
Asli N. Goktug
*Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, U.S.A.
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Ayesha Elias;
Ayesha Elias
*Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, U.S.A.
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Jing Wu;
Jing Wu
*Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, U.S.A.
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Darren Saunders;
Darren Saunders
†Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst NSW 2010, Australia
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Taosheng Chen
Taosheng Chen
1
*Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, U.S.A.
1To whom correspondence should be addressed (email taosheng.chen@stjude.org).
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Publisher: Portland Press Ltd
Received:
April 19 2013
Revision Received:
January 17 2014
Accepted:
January 20 2014
Accepted Manuscript online:
January 20 2014
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2014 Biochemical Society
2014
Biochem J (2014) 459 (1): 193–203.
Article history
Received:
April 19 2013
Revision Received:
January 17 2014
Accepted:
January 20 2014
Accepted Manuscript online:
January 20 2014
Citation
Su Sien Ong, Asli N. Goktug, Ayesha Elias, Jing Wu, Darren Saunders, Taosheng Chen; Stability of the human pregnane X receptor is regulated by E3 ligase UBR5 and serine/threonine kinase DYRK2. Biochem J 1 April 2014; 459 (1): 193–203. doi: https://doi.org/10.1042/BJ20130558
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