2020年6月8日，美国弗雷德·哈钦森癌症研究中心Slobodan Beronja研究团队在《细胞-干细胞》杂志在线发表论文，宣布发现细胞命运调节因子的选择性翻译介导了细胞对广泛致癌应激的耐受。

研究人员揭示了一种动态翻译机制，该机制通过协调致癌HRAS诱导的过度增殖与祖细胞自我更新的丧失来抑制细胞的异常生长和肿瘤发生。研究人员确定了翻译启动子eIF2B5是HRAS增殖和细胞命运选择的主要协同调节因子。通过结合体内核糖体谱与遗传筛选，研究人员提供了直接证据表明癌基因诱导的祖细胞自我更新丧失是由eIF2B5介导的基因泛素化调控的。

泛素连接酶FBXO32可特异性抑制表皮更新而不影响整体增殖，从而在维持正常组织生长的同时抑制了HRAS诱导的肿瘤发生。因此，癌基因驱动的翻译并不一定促进肿瘤发生，而是可以通过控制祖细胞的命运来延长正常组织的生长，从而调控广泛的致癌应激。

据了解，人皮肤耐受了难以想象的高致癌病变风险。尽管成年表皮细胞可以抑制单个突变体克隆的扩增，但尚不清楚其对更广泛的组织癌基因激活耐受的机制。

附：英文原文

Title: Selective Translation of Cell Fate Regulators Mediates Tolerance to Broad Oncogenic Stress

Author: Elise Y. Cai, Megan N. Kufeld, Samantha Schuster, Sonali Arora, Madeline Larkin, Alexandre A. Germanos, Andrew C. Hsieh, Slobodan Beronja

Issue&Volume: 2020-06-08

Abstract: Human skin tolerates a surprisingly high burden of oncogenic lesions. Although adultepidermis can suppress the expansion of individual mutant clones, the mechanisms behindtolerance to oncogene activation across broader regions of tissue are unclear. Here,we uncover a dynamic translational mechanism that coordinates oncogenic HRAS-inducedhyperproliferation with loss of progenitor self-renewal to restrain aberrant growthand tumorigenesis. We identify translation initiator eIF2B5 as a central co-regulatorof HRAS proliferation and cell fate choice. By coupling in vivo ribosome profiling with genetic screening, we provide direct evidence that oncogene-inducedloss of progenitor self-renewal is driven by eIF2B5-mediated translation of ubiquitinationgenes. Ubiquitin ligase FBXO32 specifically inhibits epidermal renewal without affectingoverall proliferation, thus restraining HRAS-driven tumorigenesis while maintainingnormal tissue growth. Thus, oncogene-driven translation is not necessarily inherentlytumor promoting but instead can manage widespread oncogenic stress by steering progenitorfate to prolong normal tissue growth.

DOI: 10.1016/j.stem.2020.05.007

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(20)30205-8