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Stability of the human pregnane X receptor is regulated by E3 ligase UBR5 and serine/threonine kinase DYRK2.
- Source :
-
Biochemical Journal . 4/1/2014, Vol. 459 Issue 1, following p193-203. 12p. - Publication Year :
- 2014
-
Abstract
- 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, where as the rescue ofUBR5 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 posttranslational 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. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 02646021
- Volume :
- 459
- Issue :
- 1
- Database :
- Academic Search Index
- Journal :
- Biochemical Journal
- Publication Type :
- Academic Journal
- Accession number :
- 98505600
- Full Text :
- https://doi.org/10.1042/BJ20130558