Cooperation between fibroblast growth factor receptor-4 and ErbB2 in regulation of cyclin D1 translation
Cooperation between fibroblast growth factor receptor-4 and ErbB2 in regulation of cyclin D1 translation
复制标题
成纤维细胞生长因子受体-4 和 ErbB2 在调节细胞周期蛋白 D1 翻译过程中的合作
DOI：
10.1074/jbc.m404252200
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发表时间：
2004-11-26
影响因子：
4.8
通讯作者：
Hynes, NE
中科院分区：
文献类型：
--
作者：
Koziczak, M;Hynes, NE
ErbB2或成纤维细胞生长因子受体-4 （FGFR-4）表达和活性的改变发生在相当一部分乳腺癌中。由于信号分子和信号通路共同驱动癌症进展，同时靶向多种信号通路是一种很有吸引力的治疗策略。考虑到这一点，我们分别检测了乳腺肿瘤细胞对ErbB2和FGFR抑制剂PKI166和PD173074的敏感性。同时阻断MDA-MB-453肿瘤细胞中的ErbB2和FGFR-4具有比单独抑制剂治疗更强的抗增殖作用。对细胞周期调节因子的研究揭示了一种新的翻译介导机制，即ErbB2和FGFR-4协同调节周期蛋白D1水平。我们的研究结果表明，FGFR-4和ErbB2分别通过MAPK和磷脂酰肌醇3-激酶/蛋白激酶B途径，都有助于维持雷帕霉素翻译途径的哺乳动物靶点的组成活性。这些受体的双重抑制强烈阻断了S6激酶1 （S6K1）的活性和细胞周期蛋白D1的翻译，细胞周期蛋白D1 mRNA与多体的关联减少证明了这一点。活性蛋白激酶B或活性S6K1的异位表达消除了双抑制剂介导的cyclin D1表达下调，表明FGFR-4/ErbB2信号靶点在调节cyclin D1翻译中的重要性。S6K1在这一过程中起核心作用，因为小干扰rna靶向的S6K1耗竭导致细胞S6K1活性降低，从而抑制cyclin D1的表达。因此，我们提出了一种新的机制来控制ErbB2和FGFR-4联合活性下游的cyclin D1表达，该机制涉及s6k1介导的翻译。
Alterations in ErbB2 or fibroblast growth factor receptor-4 (FGFR-4) expression and activity occur in a significant fraction of breast cancers. Because signaling molecules and pathways cooperate to drive cancer progression, simultaneous targeting of multiple pathways is an appealing therapeutic strategy. With this in mind, we examined breast tumor cells for their sensitivity to the ErbB2 and FGFR inhibitors, PKI166 and PD173074, respectively. Simultaneous blocking of ErbB2 and FGFR-4 in MDA-MB-453 tumor cells had a stronger antiproliferative effect than treatment with individual inhibitors. Examination of cell cycle regulators revealed a novel translation-mediated mechanism whereby ErbB2 and FGFR-4 cooperate to regulate cyclin D1 levels. Our results showed that FGFR-4 and ErbB2 via the MAPK and the phosphatidylinositol 3-kinase/protein kinase B pathways, respectively, both contribute to the maintenance of constitutive activity of the mammalian target of rapamycin translational pathway. Dual inhibition of these receptors strongly blocked S6 kinase 1 (S6K1) activity and cyclin D1 translation, as attested by a decrease in cyclin D1 mRNA association with polysomes. Ectopic expression of active protein kinase B or active S6K1 abrogated the dual inhibitor-mediated down-regulation of cyclin D1 expression, demonstrating the importance of these FGFR-4/ErbB2 signaling targets in regulating cyclin D1 translation. S6K1 has the central role in this process, since small interfering RNA-targeted S6K1 depletion led to a decrease in cellular S6K1 activity and, as a consequence, repression of cyclin D1 expression. Thus, we propose a novel mechanism for controlling cyclin D1 expression downstream of combined activity of ErbB2 and FGFR-4 that involves S6K1-mediated translation.