RNA-binding Protein Insulin-like Growth Factor mRNA-binding Protein 3 (IMP-3) Promotes Cell Survival via Insulin-like Growth Factor II Signaling after Ionizing Radiation
RNA-binding Protein Insulin-like Growth Factor mRNA-binding Protein 3 (IMP-3) Promotes Cell Survival via Insulin-like Growth Factor II Signaling after Ionizing Radiation
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DOI：
10.1074/jbc.m111.263913
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发表时间：
2011-09-09
影响因子：
4.8
通讯作者：
Brewer, Gary
中科院分区：
文献类型：
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作者：
Liao, Baisong;Hu, Yan;Brewer, Gary
电离辐射(IR)诱导促凋亡基因表达程序，抑制细胞存活。这些程序通常涉及与其信使核糖核酸靶标相关联的RNA结合蛋白，以引起信使核糖核酸稳定性和/或翻译的变化。RNA结合蛋白IMP-3是一种癌胎儿蛋白，在许多人类恶性肿瘤中过度表达。IMP-3的丰度与肿瘤的侵袭性和预后不良有关。因此，IMP-3被证明是外科病理学中一个非常重要的生物标记物。在其众多的信使核糖核酸靶点中，IMP-3结合并促进胰岛素样生长因子II(IGFII)信使核糖核酸的翻译。我们早期的研究表明，通过siRNAs降低IMP-3的丰度可以抑制K562慢性粒细胞白血病细胞的增殖，这是由于IGF-II生物合成减少所致。然而，IMP-3在细胞凋亡中的作用尚不清楚。在此，我们以IR诱导的K562细胞凋亡为模型，探讨IMP-3在细胞存活中的作用。用siRNA敲除IMP-3增加了细胞对IR诱导的凋亡的敏感性，并导致IGF-II产生减少。基因报告分析表明，在细胞凋亡过程中，IMP-3通过IGFII基因5‘端非编码区促进翻译。最后，用重组IGF-II培养IR处理的细胞，部分逆转了IMP-3在IR诱导的细胞凋亡中的作用。综上所述，这些结果表明，IMP-3部分通过IGF-II途径促进IR后细胞的存活。因此，IMP-3可能作为一个新的药物靶点来增加CML细胞或其他癌症对IR治疗的敏感性。
Ionizing radiation (IR) induces proapoptotic gene expression programs that inhibit cell survival. These programs often involve RNA-binding proteins that associate with their mRNA targets to elicit changes in mRNA stability and/or translation. The RNA-binding protein IMP-3 is an oncofetal protein overexpressed in many human malignancies. IMP-3 abundance correlates with tumor aggressiveness and poor prognosis. As such, IMP-3 is proving to be a highly significant biomarker in surgical pathology. Among its many mRNA targets, IMP-3 binds to and promotes translation of insulin-like growth factor II (IGFII) mRNA. Our earlier studies showed that reducing IMP-3 abundance with siRNAs reduced proliferation of human K562 chronic myeloid leukemia cells because of reduced IGF-II biosynthesis. However, the role of IMP-3 in apoptosis is unknown. Here, we have used IR-induced apoptosis of K562 cells as a model to explore a role for IMP-3 in cell survival. Knockdown of IMP-3 with siRNA increased susceptibility of cells to IR-induced apoptosis and led to reduced IGF-II production. Gene reporter assays revealed that IMP-3 acts through the 5' UTR of IGFII mRNA during apoptosis to promote translation. Finally, culture of IR-treated cells with recombinant IGF-II partially reversed the effects of IMP-3 knockdown on IR-induced apoptosis. Together, these results indicate that IMP-3 acts in part through the IGF-II pathway to promote cell survival in response to IR. Thus, IMP-3 might serve as a new drug target to increase sensitivity of CML cells or other cancers to IR therapy.