Tripartite Motif Containing 24 Acts as a Novel Coactivator of the Constitutive Active/Androstane Receptor

Drug Metab Dispos. 2018 Jan;46(1):46-52. doi: 10.1124/dmd.117.077693. Epub 2017 Nov 3.

Abstract

The constitutive androstane receptor (CAR) is a nuclear receptor that acts as a transcription factor for a variety of genes, including genes encoding xenobiotic, steroid, and drug-metabolizing enzymes and transporters. Transactivation of a target gene by a transcription factor is generally mediated through the concerted and stepwise recruitment of various proteins termed coregulators, including coactivators and corepressors. In this study, TRIM24 (also known as transcriptional intermediary factor 1 alpha) was found to interact with the CAR. TRIM24 enhanced the CAR-dependent transactivation in reporter assays using the direct repeat-4 motif, a binding site of the CAR. This enhancement was synergistically augmented in the presence of steroid receptor coactivator (SRC) 1 or SRC2, both of which are coactivators of the CAR. In addition, TRIM24 was recruited to the CAR-binding element of the CYP2B6 promoter together with the CAR. We also noted that knockdown of TRIM24 suppressed CAR-induced CYP2B6 mRNA expression in HepTR/CAR and HepaRG cells and suppressed CAR-induced CYP3A4 mRNA expression in HepaRG cells but not HepTR/CAR cells. From these results, we suggest that TRIM24 is a novel coactivator of the CAR that is involved in cell- and/or promoter- selective transactivation.

MeSH terms

  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cytochrome P-450 CYP2B6 / genetics
  • Cytochrome P-450 CYP2B6 / metabolism
  • Cytochrome P-450 CYP3A / genetics
  • Cytochrome P-450 CYP3A / metabolism
  • Gene Knockdown Techniques
  • Hep G2 Cells
  • Humans
  • Nuclear Receptor Coactivator 1 / genetics
  • Nuclear Receptor Coactivator 1 / metabolism
  • Nuclear Receptor Coactivator 2 / genetics
  • Nuclear Receptor Coactivator 2 / metabolism
  • Promoter Regions, Genetic / genetics
  • RNA Interference
  • RNA, Messenger / metabolism
  • RNA, Small Interfering / metabolism
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Transcriptional Activation*

Substances

  • Carrier Proteins
  • NCOA2 protein, human
  • Nuclear Receptor Coactivator 2
  • RNA, Messenger
  • RNA, Small Interfering
  • Receptors, Cytoplasmic and Nuclear
  • TRIM24 protein, human
  • constitutive androstane receptor
  • CYP2B6 protein, human
  • Cytochrome P-450 CYP2B6
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • NCOA1 protein, human
  • Nuclear Receptor Coactivator 1