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Molecular and Cellular Biology, February 2000, p. 957-970, Vol. 20, No. 3
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Orphan Receptor COUP-TF Is Required for Induction of Retinoic Acid Receptor beta , Growth Inhibition, and Apoptosis by Retinoic Acid in Cancer Cells

Bingzhen Lin, Guo-quan Chen, Dongmei Xiao, Siva Kumar Kolluri, Xihua Cao, Hong Su, and Xiao-kun Zhang*

Cancer Research Center, The Burnham Institute, La Jolla, California 92037

Received 31 August 1999/Returned for modification 1 October 1999/Accepted 5 November 1999

Retinoic acid receptor beta  (RARbeta ) plays a critical role in mediating the anticancer effects of retinoids. Expression of RARbeta is highly induced by retinoic acid (RA) through a RA response element (beta RARE) that is activated by heterodimers of RARs and retinoid X receptors (RXRs). However, RARbeta induction is often lost in cancer cells despite expression of RARs and RXRs. In this study, we provide evidence that orphan receptor COUP-TF is required for induction of RARbeta expression, growth inhibition, and apoptosis by RA in cancer cells. Expression of COUP-TF correlates with RARbeta induction in a variety of cancer cell lines. In addition, stable expression of COUP-TF in COUP-TF-negative cancer cells restores induction of RARbeta expression, growth inhibition, and apoptosis by RA, whereas inhibition of COUP-TF by expression of COUP-TF antisense RNA represses the RA effects. In a transient transfection assay, COUP-TF strongly induced transcriptional activity of the RARbeta promoter in a RA- and RARalpha -dependent manner. By mutation analysis, we demonstrate that the effect of COUP-TF requires its binding to a DR-8 element present in the RARbeta promoter. The binding of COUP-TF to the DR-8 element synergistically increases the RA-dependent RARalpha transactivation function by enhancing the interaction of RARalpha with its coactivator CREB binding protein. These results demonstrate that COUP-TF, by serving as an accessory protein for RARalpha to induce RARbeta expression, plays a critical role in regulating the anticancer activities of retinoids.

* Corresponding author. Mailing address: The Burnham Institute, Cancer Research 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, February 2000, p. 957-970, Vol. 20, No. 3
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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