p21WAF1/CIP1 is a common transcriptional target of retinoid receptors: Pleiotropic regulatory mechanism through Retinoic Acid Receptor (RAR)/Retinoid X Receptor (RXR) heterodimer and RXR/RXR homodimer

Takemi Tanaka, Kwang S. Suh, Angela M. Lo, Luigi M. De Luca

Research output: Contribution to journalArticlepeer-review

Abstract

The divergent response and the molecular mechanisms underlying the anti-cancer effects of retinoid X receptor (RXR) ligand (rexinoid) therapy are poorly understood. This study demonstrates that ligand-activated RXR homodimer facilitated G1 arrest by up-regulation of p21 in vitro and in vivo but failed to induce G1 arrest when p21 expression was blocked by p21 small interfering RNA. RXR ligand-dependent p21 up-regulation was transcriptionally controlled through the direct binding of RXR homodimers to two consecutive retinoid X response elements in the p21 promoter. Structural overlap of a retinoic acid response element with these retinoid X response elements led to a high affinity binding of retinoic acid receptor/RXR heterodimer to the retinoic acid response element, resulting in the prevention of RXR ligand-mediated p21 transactivation. These data show that p21 is a potential and novel molecular target for RXR ligandmediated anti-cancer therapy and that the expression level of retinoic acid receptor and RXR in tumors may be crucial to induce p21-mediated cell growth arrest in RXR ligand therapy.

Original languageEnglish (US)
Pages (from-to)29987-29997
Number of pages11
JournalJournal of Biological Chemistry
Volume282
Issue number41
DOIs
StatePublished - Oct 12 2007

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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