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Updated: May 6, 2026

Reverse Yeast Two-hybrid System to Identify Mammalian Nuclear Receptor Residues that Interact with Ligands and/or Antagonists
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Reverse Yeast Two-hybrid System to Identify Mammalian Nuclear Receptor Residues that Interact with Ligands and/or Antagonists

Published on: November 16, 2013

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Arsenic trioxide inhibits nuclear receptor function via SEK1/JNK-mediated RXRalpha phosphorylation

Koren K Mann1, Alessandra M S Padovani, Qi Guo

  • 1Montréal Centre for Experimental Therapeutics in Cancer, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, McGill University, Montréal, Québec, Canada.

The Journal of Clinical Investigation
|September 27, 2005
PubMed

Insights

Arsenic trioxide (As2O3) inhibits retinoic acid receptor signaling in acute promyelocytic leukemia cells by phosphorylating RXRalpha. This phosphorylation, particularly at serine 32, blocks gene transcription and may inform new therapeutic strategies.

Area of Science:

  • Molecular Biology
  • Oncology
  • Pharmacology

Background:

  • Acute promyelocytic leukemia (APL) is treated with arsenic trioxide (As2O3) and retinoic acid.
  • Previous studies indicated potential antagonism between As2O3 and retinoic acid in vitro.
  • Nuclear receptors play critical roles in cellular signaling and gene regulation.

Purpose of the Study:

  • To investigate the molecular mechanisms by which As2O3 affects nuclear receptor signaling, specifically the retinoic acid receptor (RAR).
  • To determine if As2O3-induced inhibition of transcription is mediated by phosphorylation of the retinoid X receptor alpha (RXRalpha).
  • To explore the role of c-Jun N-terminal kinase (JNK) in As2O3-induced effects on RXRalpha.

Main Methods:

  • In vitro transcription assays to measure ligand-induced receptor activity.
  • In vivo labeling and phosphoamino acid analysis to detect RXRalpha phosphorylation.
  • Pharmacologic and genetic inhibition of JNK signaling pathways.
  • Mutational analysis of RXRalpha to identify key phosphorylation sites.

Main Results:

  • As2O3 inhibited ligand-induced transcription of RAR and other nuclear receptors that heterodimerize with RXRalpha.
  • As2O3 specifically phosphorylated RXRalpha on serine residues in the N-terminal ABC region.
  • Inhibition of JNK activation reduced As2O3-induced RXRalpha phosphorylation and blocked transcriptional inhibition.
  • Phosphorylation of serine 32 (S32) on RXRalpha was found to be primarily responsible for the observed inhibition of transcription.

Conclusions:

  • As2O3 inhibits RXRalpha-mediated transcription through direct phosphorylation of RXRalpha, particularly at S32.
  • JNK signaling is involved in As2O3-induced RXRalpha phosphorylation and subsequent transcriptional inhibition.
  • These findings offer insights into the development of combined chemotherapeutic regimens for APL and the molecular basis of arsenic-induced carcinogenesis.

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