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First published online 19 October 2004
doi: 10.1242/jcs.01474

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RXR acts as a carrier for TR3 nuclear export in a 9-cis retinoic acid-dependent manner in gastric cancer cells

Xiao-Feng Lin^*, Bi-Xing Zhao^*, Hang-Zhi Chen, Xiao-Feng Ye, Chao-Yi Yang, Hai-Ying Zhou, Ming-Qing Zhang, Sheng-Cai Lin and Qiao Wu

Key Laboratory of the Ministry of Education for Cell Biology and Tumor Cell Engineering, School of Life Sciences, Xiamen University, Xiamen, Fujian Province, 361005, China

Author for correspondence (e-mail: xgwu{at}xmu.edu.cn)

Accepted 30 July 2004

Retinoid X receptor (RXR) plays a crucial role in the cross talk between retinoid receptors and other hormone receptors including the orphan receptor TR3, forming different heterodimers that transduce diverse steroid/thyroid hormone signaling. Here we show that RXR exhibits nucleocytoplasmic shuttling in MGC80-3 gastric cancer cells and that RXR shuttling is energy-dependent through a nuclear pore complex (NPC)-mediated pathway for its import and an intact DNA binding domain-mediated pathway for its export. In the presence of its ligand 9-cis retinoic acid, RXR was almost exclusively located in the cytoplasm. More importantly, we also show that RXR acts as a carrier to assist translocation of TR3, which plays an important role in apoptosis. Both RXR and TR3 colocalized in the nucleus; however, upon stimulation by 9-cis retinoic acid they cotranslocated to the cytoplasm and then localized in the mitochondria. TR3 export depends on RXR, as in living cells GFP-TR3 alone did not result in export from the nucleus even in the presence of 9-cis retinoic acid, whereas GFP-TR3 cotransfected with RXR was exported out of the nucleus in response to 9-cis retinoic acid. Moreover, specific reduction of RXR levels caused by anti-sense RXR abolished TR3 nuclear export. In contrast, specific knockdown of TR3 by antisense-TR3 or TR3-siRNA did not affect RXR shuttling. These results indicate that RXR is responsible for TR3 nucleocytoplasmic translocation, which is facilitated by the RXR ligand 9-cis retinoic acid. In addition, mitochondrial TR3, but not RXR, was critical for apoptosis, as TR3 mutants that were distributed in the mitochondria induced apoptosis in the presence or absence of 9-cis retinoic acid. These data reveal a novel aspect of RXR function, in which it acts as a carrier for nucleocytoplasmic translocation of orphan receptors.

Key words: Retinoid X receptor (RXR), Orphan receptor TR3, 9-cis retinoic acid, Nucleocytoplasmic translocation, Gastric cancer cells

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