Nature：靶向攻击致癌基因新方法

　　

生物通报道，美国加州大学生化与生物物理学系，加州大学Helen Diller家族癌症综合研究中心，巴西圣保罗大学细胞疗法研究中心的科学家找到一种抑制癌症基因的新方法，研究成果公布在最新的Nature上。

 

Myc致癌基因具有调控几种蛋白的合成，包括核糖体蛋白，翻译起始因子蛋白，RNA聚合酶Ⅲ和核糖体DNA。Myc致癌基因增强这些蛋白的表达量会导致发生一系列的癌变。在本研究中，研究小组用核糖体蛋白杂合子小鼠作为遗传手段修复Eμ-Myc/+转基因小鼠的蛋白合成水平使之达到正常的水平，并且在这个过程研究小组发现Myc的致癌潜能被抑制。

 

研究发现Myc能加强蛋白合成，使得细胞的形态增大，并且加剧细胞分裂，使细胞变为不依赖细胞分裂周期靶位而无限制复制下去。此外，当蛋白过度合成的情况得到缓解恢复正常水平后，过度表达Myc的癌前细胞就会被机体的细胞凋亡程序清除干净。

 

在核糖体进入位点上有个蛋白合成的“开关”，Myc活动过强就会导致这个开关不受控制，导致细胞无限制地有丝分裂，发生癌变。细胞内也发生一系列变化，基因组失去稳定性。

 

研究者认为，翻译控制发生的变化会影响基因表达，基因组的稳定性，翻译控制发生变化还可能诱发细胞癌变。该文章也从后基因组水平揭示了癌症形成的过程。

 

原文摘要：Suppression of Myc oncogenic activity by ribosomal protein haploinsufficiency

【Abstract】

The Myc oncogene regulates the expression of several components of the protein synthetic machinery, including ribosomal proteins, initiation factors of translation, RNA polymerase III and ribosomal DNA1, 2. Whether and how increasing the cellular protein synthesis capacity affects the multistep process leading to cancer remains to be addressed. Here we use ribosomal protein heterozygote mice as a genetic tool to restore increased protein synthesis in E-Myc/+ transgenic mice to normal levels, and show that the oncogenic potential of Myc in this context is suppressed. Our findings demonstrate that the ability of Myc to increase protein synthesis directly augments cell size and is sufficient to accelerate cell cycle progression independently of known cell cycle targets transcriptionally regulated by Myc. In addition, when protein synthesis is restored to normal levels, Myc-overexpressing precancerous cells are more efficiently eliminated by programmed cell death. Our findings reveal a new mechanism that links increases in general protein synthesis rates downstream of an oncogenic signal to a specific molecular impairment in the modality of translation initiation used to regulate the expression of selective messenger RNAs. We show that an aberrant increase in cap-dependent translation downstream of Myc hyperactivation specifically impairs the translational switch to internal ribosomal entry site (IRES)-dependent translation that is required for accurate mitotic progression. Failure of this translational switch results in reduced mitotic-specific expression of the endogenous IRES-dependent form of Cdk11 (also known as Cdc2l and PITSLRE)3, 4, 5, which leads to cytokinesis defects and is associated with increased centrosome numbers and genome instability in E-Myc/+ mice. When accurate translational control is re-established in E-Myc/+ mice, genome instability is suppressed. Our findings demonstrate how perturbations in translational control provide a highly specific outcome for gene expression, genome stability and cancer initiation that have important implications for understanding the molecular mechanism of cancer formation at the post-genomic level.