Retinoic Acid Receptor/Retinoid X Receptor Heterodimers Can Be Activated through Both Subunits Providing a Basis for Synergistic Transactivation and Cellular Differentiation

doi:10.1074/jbc.272.14.9443

Retinoic Acid Receptor/Retinoid X Receptor Heterodimers Can Be Activated through Both Subunits Providing a Basis for Synergistic Transactivation and Cellular Differentiation*

From the ^‡ Laboratory of Tumor Biology, Department of Pathology, Uppsala University, S-751 85 Uppsala, Sweden and the
^§ Ludwig Institute for Cancer Research, Box 240, S-171 77 Stockholm, Sweden

^¶ To whom correspondence should be addressed. Tel.: 46-8-728-71-06; Fax: 46-8-33-28-12; E-mail: Thomas.Perlmann{at}licr.ki.se

Abstract

The receptor for 9-cis-retinoic acid, retinoid X receptor (RXR), forms heterodimers with several nuclear receptors, including the receptor for all-trans-retinoic acid, RAR. Previous studies have shown that retinoic acid receptor can be activated in RAR/RXR heterodimers, whereas RXR is believed to be a silent co-factor. In this report we show that efficient growth arrest and differentiation of the human monocytic cell line U-937 require activation of both RAR and RXR. Also, we demonstrate that the allosteric inhibition of RXR is not obligatory and that RXR can be activated in the RAR/RXR heterodimer in the presence of RAR ligands. Remarkably, RXR inhibition by RAR can also be relieved by an RAR antagonist. Moreover, the dose response of RXR agonists differ between RXR homodimers and RAR/RXR heterodimers, indicating that these complexes are pharmacologically distinct. Finally, the AF2 activation domain of both subunits contribute to activation even if only one of the receptors is associated with ligand. Our data emphasize the importance of signaling through both subunits of a heterodimer in the physiological response to retinoids and show that the activity of RXR is dependent on both the identity and the ligand binding state of its partner.

Footnotes

↵* This work was supported by Swedish Medical Research Council and by the Children's Cancer Foundation of Sweden, the Swedish Cancer Society, and the Hans von Kantzow Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
↵¹ The abbreviations used are:

RA

retinoic acid

atRA

all-trans-RA

9cRA

9-cis-RA

LBD

ligand binding domain

AF2

activation function 2

RAR

RA receptor

RXR

retinoid X receptor

TR

thyroid hormone receptor

VDR

vitamin D3 receptor

RARE

RA response element

β RE

RARE from the RARβ₂ promoter

PPAR

peroxisome proliferator-activated receptor
- Received November 15, 1996.
- Revision received December 17, 1996.