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Molecular and Cellular Biology, November 2004, p. 9705-9725, Vol. 24, No. 22
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.22.9705-9725.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Retinoid X Receptor Regulates Nur77/Thyroid Hormone Receptor 3-Dependent Apoptosis by Modulating Its Nuclear Export and Mitochondrial Targeting

Xihua Cao, Wen Liu, Feng Lin, Hui Li, Siva Kumar Kolluri, Bingzhen Lin, Young-hoon Han, Marcia I. Dawson, and Xiao-kun Zhang*

Cancer Center, The Burnham Institute, La Jolla, California

Received 11 March 2004/ Returned for modification 27 May 2004/ Accepted 10 August 2004

Retinoid X receptor (RXR) plays a central role in the regulation of intracellular receptor signaling pathways by acting as a ubiquitous heterodimerization partner of many nuclear receptors, including the orphan receptor Nur77 (also known as thyroid hormone receptor 3 or NGFI-B), which translocates from the nucleus to mitochondria, where it interacts with Bcl-2 to induce apoptosis. Here, we report that RXR{alpha} is required for nuclear export and mitochondrial targeting of Nur77 through their unique heterodimerization that is mediated by dimerization interfaces located in their DNA-binding domain. The effects of RXR{alpha} are attributed to a putative nuclear export sequence (NES) present in its carboxyl-terminal region. RXR{alpha} ligands suppress NES activity by inducing RXR{alpha} homodimerization or altering RXR{alpha}/Nur77 heterodimerization. The RXR{alpha} NES is also silenced by RXR{alpha} heterodimerization with retinoic acid receptor or vitamin D receptor. Consistently, we were able to show that the mitochondrial targeting of the RXR{alpha}/Nur77 heterodimer and its induction of apoptosis are potently inhibited by RXR ligands. Together, our results reveal a novel nongenotropic function of RXR{alpha} and its involvement in the regulation of the Nur77-dependent apoptotic pathway.

* Corresponding author. Mailing address: The Burnham Institute, Cancer Center, 10901 N. Torrey Pines Rd., La Jolla, CA 92037. Phone: (858) 646-3141. Fax: (858) 646-3195. E-mail: xzhang{at}burnham-inst.org.

Molecular and Cellular Biology, November 2004, p. 9705-9725, Vol. 24, No. 22
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.22.9705-9725.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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