Rapid apoptosis induction by IGFBP-3 involves an insulin-like growth factor-independent nucleomitochondrial translocation of RXRα/Nur77
Rapid apoptosis induction by IGFBP-3 involves an insulin-like growth factor-independent nucleomitochondrial translocation of RXRα/Nur77
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DOI：
10.1074/jbc.m412757200
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发表时间：
2005-04-29
影响因子：
4.8
通讯作者：
Cohen, P
中科院分区：
文献类型：
--
作者：
Lee, KW;Ma, LQ;Cohen, P
胰岛素样生长因子结合蛋白-3 （IGFBP-3）通过其结合胰岛素样生长因子（igf）的能力以及与其他分子（包括类视黄醇X受体α (RXR α)）结合的igf非依赖性作用诱导细胞凋亡。在这里，我们描述了作为对IGFBP-3的响应，RXR α结合伴侣核受体Nur77迅速经历从细胞核到线粒体的易位，在6小时内启动凋亡级联，导致caspase激活。这种易位是1型IGF受体信号独立事件，因为IGFBP-3诱导r细胞中的Nur77易位。IGFBP-3和Nur77在诱导细胞凋亡中具有协同作用。将GFP-Nur77转染到RXR α野生型和敲除小鼠胚胎成纤维细胞中，随后用IGFBP-3处理，结果表明，IGFBP-3诱导的Nur77易位和凋亡需要RXR α。在22RV1细胞裂解液中添加IGFBP-3可增强GST-RXR α“拉下”Nur77的能力，过表达IGFBP-3可增强线粒体RXR α的积累。这种独特的非基因性核通路支持IGFBP-3作为一种新的多室信号分子参与诱导恶性细胞凋亡的新兴作用。
Insulin-like growth factor-binding protein-3 (IGFBP-3) induces apoptosis by its ability to bind insulin-like growth factors (IGFs) as well as its IGF-independent effects involving binding to other molecules including the retinoid X receptor-alpha (RXR alpha). Here we describe that in response to IGFBP-3, the RXR alpha binding partner nuclear receptor Nur77 rapidly undergoes translocation from the nucleus to the mitochondria, initiating an apoptotic cascade resulting in caspase activation within 6 h. This translocation is a type 1 IGF receptor-signaling independent event as IGFBP-3 induces Nur77 translocation in R-cells. IGFBP-3 and Nur77 are additive in inducing apoptosis. GFP-Nur77 transfection into RXR alpha wildtype and knock-out mouse embryonic fibroblasts and subsequent treatment with IGFBP-3 show that RXR alpha is required for IGFBP-3-induced Nur77 translocation and apoptosis. Addition of IGFBP-3 to 22RV1 cell lysates enhanced the ability of GST-RXR alpha to "pull down" Nur77, and overexpression of IGFBP-3 enhanced the accumulation of mitochondrial RXR alpha. This unique nongenotropic nuclear pathway supports an emerging role for IGFBP-3 as a novel, multicompartmental signaling molecule involved in induction of apoptosis in malignant cells.