RXRalpha acts as a carrier for TR3 nuclear export in a 9-cis retinoic acid-dependent manner in gastric cancer cells.
RXRalpha acts as a carrier for TR3 nuclear export in a 9-cis retinoic acid-dependent manner in gastric cancer cells.
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发表时间：
2004
影响因子：
4
通讯作者：
Xiao-feng Lin;Bi-xing Zhao;Hang Chen;Xiao-feng Ye;Chao-yi Yang;Hai-Ying Zhou;Ming-qing Zhang;Sheng-Cai Lin;Qiao Wu
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作者：
Xiao-feng Lin;Bi-xing Zhao;Hang Chen;Xiao-feng Ye;Chao-yi Yang;Hai-Ying Zhou;Ming-qing Zhang;Sheng-Cai Lin;Qiao Wu
类维生素A X受体（RXR）在类维生素A受体与包括孤儿受体TR 3在内的其他激素受体之间的串扰中起着至关重要的作用，形成不同的异源二聚体，从而抑制不同的类固醇/甲状腺激素信号传导。在这里，我们表明，RXR α在MGC 80 -3胃癌细胞中表现出核质穿梭，并且RXR α穿梭是能量依赖性的，通过核孔复合物（NPC）介导的途径进行输入，并通过完整的DNA结合结构域介导的途径进行输出。在其配体9-顺式维甲酸的存在下，RXR α几乎完全位于细胞质中。更重要的是，我们还发现RXR α作为载体协助TR 3的易位，TR 3在细胞凋亡中起着重要作用。RXR α和TR 3共定位在细胞核中，然而，在9-顺式视黄酸刺激后，它们共易位到细胞质中，然后定位在线粒体中。TR 3输出依赖于RXR α，因为在活细胞中，即使在9-顺式视黄酸存在下，单独的GFP-TR 3也不会导致从细胞核输出，而与RXR α共转染的GFP-TR 3响应于9-顺式视黄酸而输出到细胞核外。此外，由反义RXR α引起的RXR α水平的特异性降低废除了TR 3核输出。相反，通过反义TR 3或TR 3-siRNA特异性敲低TR 3不影响RXR α穿梭。这些结果表明，RXR α是负责TR 3核质易位，这是由RXR α配体9-顺式视黄酸促进。此外，线粒体TR 3，而不是RXR α，是细胞凋亡的关键，因为TR 3突变体，分布在线粒体诱导细胞凋亡的存在或不存在的9-顺式视黄酸。这些数据揭示了RXR α功能的一个新方面，即它作为孤儿受体核质易位的载体。
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 RXRalpha exhibits nucleocytoplasmic shuttling in MGC80-3 gastric cancer cells and that RXRalpha 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, RXRalpha was almost exclusively located in the cytoplasm. More importantly, we also show that RXRalpha acts as a carrier to assist translocation of TR3, which plays an important role in apoptosis. Both RXRalpha 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 RXRalpha, 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 RXRalpha was exported out of the nucleus in response to 9-cis retinoic acid. Moreover, specific reduction of RXRalpha levels caused by anti-sense RXRalpha abolished TR3 nuclear export. In contrast, specific knockdown of TR3 by antisense-TR3 or TR3-siRNA did not affect RXRalpha shuttling. These results indicate that RXRalpha is responsible for TR3 nucleocytoplasmic translocation, which is facilitated by the RXRalpha ligand 9-cis retinoic acid. In addition, mitochondrial TR3, but not RXRalpha, 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 RXRalpha function, in which it acts as a carrier for nucleocytoplasmic translocation of orphan receptors.