Inhibitory cross-talk between estrogen receptor (ER) and constitutively activated androstane receptor (CAR). CAR inhibits ER-mediated signaling pathway by squelching p160 coactivators

J Biol Chem. 2002 Sep 13;277(37):34626-33. doi: 10.1074/jbc.M205239200. Epub 2002 Jul 11.

Abstract

Estrogen receptor (ER) activity can be modulated by the action of other nuclear receptors. To study whether ER activity is altered by orphan nuclear receptors that mediate the cellular response to xenobiotics, cross-talk between ER and constitutive androstane receptor (CAR), steroid and xenobiotic receptor, or peroxisome proliferator-activated receptor gamma was examined in HepG2 cells. Of these receptors, CAR substantially inhibited ER-mediated transcriptional activity of the vitellogenin B1 promoter as well as a synthetic estrogen responsive element (ERE)-containing promoter. Treatment with an agonist of CAR, 1,4-bis-(2-(3,5-dichloropyridoxyl))benzene, potentiated CAR-mediated transcriptional repression. In contrast, an antagonist of CAR, androstenol, alleviated the repression effect. Although CAR interacted with the ER in solution, CAR did not interact with the ER bound to the ERE. CAR/retinoid X receptor bound to the ERE but with much lower affinity than ER. Incremental amounts of CAR elicited a progressive reduction of the ER activity induced by the p160 coactivator glucocorticoid receptor interacting protein 1 (GRIP-1). In turn, increasing amounts of GRIP-1 progressively reversed the depression of ER activity by CAR. An agonist or antagonist of CAR potentiated or alleviated, respectively, the CAR-mediated repression of the GRIP-1-enhanced ER activity, which is consistent with the ability of theses ligands to increase or decrease, respectively, the interaction of CAR with GRIP-1. A CAR mutant that did not interact with GRIP-1 did not inhibit ER-mediated transactivation. Our data demonstrate that xenobiotic nuclear receptor CAR antagonizes ER-mediated transcriptional activity by squelching limiting amounts of p160 coactivator and imply that xenobiotics may influence ER function of female reproductive physiology, cell differentiation, tumorigenesis, and lipid metabolism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Cell Line
  • Constitutive Androstane Receptor
  • Histone Acetyltransferases
  • Humans
  • Molecular Sequence Data
  • Nuclear Receptor Coactivator 1
  • Nuclear Receptor Coactivator 2
  • Receptors, Cytoplasmic and Nuclear / physiology*
  • Receptors, Estrogen / physiology*
  • Receptors, Retinoic Acid / physiology
  • Response Elements
  • Retinoid X Receptors
  • Transcription Factors / physiology*
  • Transcriptional Activation

Substances

  • Constitutive Androstane Receptor
  • NCOA2 protein, human
  • Nuclear Receptor Coactivator 2
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Estrogen
  • Receptors, Retinoic Acid
  • Retinoid X Receptors
  • Transcription Factors
  • Histone Acetyltransferases
  • NCOA1 protein, human
  • Nuclear Receptor Coactivator 1