Histology and Cell Growth, San Raffaele Scientific Institute, Milan, Italy.
Cancer Cell. 2011 Jun 14;19(6):765-75. doi: 10.1016/j.ccr.2011.04.018.
Eukaryotic Initiation Factor 6 (eIF6) controls translation by regulating 80S subunit formation. eIF6 is overexpressed in tumors. Here, we demonstrate that eIF6 inactivation delays tumorigenesis and reduces tumor growth in vivo. eIF6(+/-) mice resist to Myc-induced lymphomagenesis and have prolonged tumor-free survival and reduced tumor growth. eIF6(+/-) mice are also protected by p53 loss. Myc-driven lymphomas contain PKCβII and phosphorylated eIF6; eIF6 is phosphorylated by tumor-derived PKCβII, but not by the eIF4F activator mTORC1. Mutation of PKCβII phosphosite of eIF6 reduces tumor growth. Thus, eIF6 is a rate-limiting controller of initiation of translation, able to affect tumorigenesis and tumor growth. Modulation of eIF6 activity, independent from eIF4F complex, may lead to a therapeutical avenue in tumor therapy.
真核起始因子 6（eIF6）通过调节 80S 亚基形成来控制翻译。eIF6 在肿瘤中过度表达。在这里，我们证明 eIF6 的失活会延迟肿瘤发生并减少体内肿瘤生长。eIF6(+/-) 小鼠抵抗 Myc 诱导的淋巴瘤发生，并且具有延长的无肿瘤存活期和减少的肿瘤生长。eIF6(+/-) 小鼠也受到 p53 缺失的保护。Myc 驱动的淋巴瘤含有 PKCβII 和磷酸化的 eIF6；eIF6 被肿瘤衍生的 PKCβII 磷酸化，但不是由 eIF4F 激活剂 mTORC1 磷酸化。eIF6 的 PKCβII 磷酸化位点突变会降低肿瘤生长。因此，eIF6 是翻译起始的限速控制器，能够影响肿瘤发生和肿瘤生长。eIF6 活性的调节，独立于 eIF4F 复合物，可能为肿瘤治疗开辟治疗途径。
