ArticleThe Biochemical journal2014
Stability of the human pregnane X receptor is regulated by E3 ligase UBR5 and serine/threonine kinase DYRK2.
Article in The Biochemical journal, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 37 citations in OpenAlex.
- E3 ubiquitin ligase UBR5 modulates circadian rhythm by facilitating the ubiquitination and degradation of the key clock transcription factor BMAL1.Acta pharmacologica Sinica · 2024Article
- UBR5 promotes antiviral immunity by disengaging the transcriptional brake on RIG-I like receptors.Nature communications · 2024Article
- S-nitrosylation attenuates pregnane X receptor hyperactivity and acetaminophen-induced liver injury.JCI insight · 2024Article
- The F-box-only protein 44 regulates pregnane X receptor protein level by ubiquitination and degradation.Acta pharmaceutica Sinica. B · 2023Article
- UBR5 forms ligand-dependent complexes on chromatin to regulate nuclear hormone receptor stability.Molecular cell · 2023Article
- Molecular basis of crosstalk in nuclear receptors: heterodimerization between PXR and CAR and the implication in gene regulation.Nucleic acids research · 2022Article
- Role of ubiquitin-protein ligase UBR5 in the disassembly of mitotic checkpoint complexes.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Insights into the critical role of the PXR in preventing carcinogenesis and chemotherapeutic drug resistance.International journal of biological sciences · 2022Review
- UBR5 promotes tumor immune evasion through enhancing IFN-γ-inducedTheranostics · 2022Article
- Review
- Updating dual-specificity tyrosine-phosphorylation-regulated kinase 2 (DYRK2): molecular basis, functions and role in diseases.Cellular and molecular life sciences : CMLS · 2020Review
- Review
- The E3 ubiquitin ligase UBR5 interacts with TTC7A and may be associated with very early onset inflammatory bowel disease.Scientific reports · 2020Article
- The DYRK Family of Kinases in Cancer: Molecular Functions and Therapeutic Opportunities.Cancers · 2020Review
- UBR5 HECT domain mutations identified in mantle cell lymphoma control maturation of B cells.Blood · 2020Article
- Phosphorylation-dependent regulation of the NOTCH1 intracellular domain by dual-specificity tyrosine-regulated kinase 2.Cellular and molecular life sciences : CMLS · 2020Article
- E3 ubiquitin ligases in B-cell malignancies.Cellular immunology · 2019Review
- Drug discovery technologies to identify and characterize modulators of the pregnane X receptor and the constitutive androstane receptor.Drug discovery today · 2019Review
- RNA interference screen identifies NAA10 as a regulator of PXR transcription.Biochemical pharmacology · 2019Article
- Transcription factor ZNF148 is a negative regulator of human muscle differentiation.Scientific reports · 2017Article
Corrections and comments
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
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, 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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.