Quantitative increases in DNA binding affinity and positional effects determine 9-cis retinoic acid induced activation of the retinoid X receptorβ homodimer

Jeffrey A. Medin, Saverio Minucci, Paul H. Driggers, Insong J. Lee, Keiko Ozato

Research output: Contribution to journalArticle

Abstract

Retinoid X receptors (RXRs) exert transcriptional activities through heterodimerization with members of the nuclear hormone receptor superfamily. RXRs also act as homodimers and stimulate transcription from an RXR responsive element (RXRE) when bound to 9-cis-retinoic acid (9cRA). Here direct effects of 9cRA have been examined on biochemical and mechanistic parameters of RXRβ. It is shown that 9cRA significantly increases RXRβ homodimer binding affinity to an RXRE (Kd without ligand = 18 nM, Kd with ligand = 6 nM), while decreasing significantly the affinity of RXRβ/thyroid hormone receptor (T3Ra) heterodimer binding to the same element. Effects on other response elements are also examined. The RXRβ homodimer was found to contact both halves of the RXRE direct repeat, irrespective of the effect of added ligand, while the RXRβ/T3R(α) heterodimer contacted the element only through a specific half-site. Binding of the homodimer to the element functionally activates RXRβ, since RXRβ enhanced transcription in vitro from a specific template in a ligand-dependent fashion. In agreement, transfection of RXRβ alone (but not RXRβ/TSR(α)) led to liganddependent activation of a reporter containing the RXRE. Taken together, 9cRA facilitates functional activation of the KXRβ homodimer in an element-dependent manner.

Original languageEnglish
Pages (from-to)27-35
Number of pages9
JournalMolecular and Cellular Endocrinology
Volume105
Issue number1
DOIs
Publication statusPublished - 1994

Keywords

  • 9-cis-Retinoic acid
  • Homodimer
  • Retinoid X receptor
  • Transcriptional regulation

ASJC Scopus subject areas

  • Endocrinology
  • Endocrinology, Diabetes and Metabolism

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