真核翻译起始因子elF3A导致的翻译起始异常和相关疾病

摘要

真核生物翻译控制在细胞进程中对基因表达调控具有重要作用,能确保蛋白的迅速调节以维持细胞内稳态.真核翻译是一个多步骤的过程,包括起始、延伸、终止和核糖体循环,其中起始是限速步骤,受真核翻译起始因子(eukaryotic translation initiation factors,eIFs)调控.翻译起始缺陷将导致一系列疾病.在所有eIFs中,eIF3是最大的同时知之较少的因子.eIF3A是eIF3因子的最大亚基,其异常一方面会导致肿瘤发生,另一方面将阻止肿瘤向更高级别恶性肿瘤进展.eIF3A表达变化和突变影响肿瘤患者对铂类化疗药物的反应.此外,eIF3A与纤维化病变相关,抑制eIF3A的试剂能延缓病变进展.eIF3A在肿瘤中的双重作用可能是其在肿瘤进展的不同阶段调节不同mRNAs翻译的结果,特定阶段不同mRNAs的编码产物发挥促癌或抑癌作用.%Translation control in eukaryotes contributes significantly to gene expression regulation during cellular processes,which enables rapid changes of specific proteins to maintain cellular homeostasis.Eukaryotic translation is a multiple-step process that comprised of four phases:initiation,elongation,termination and ribosome recycling.The initiation phase is rate-limiting and orchestrated by a set of eukaryotic translation initiation factors (eIFs).Defects in translation initiation can result in a series of diseases.Among all eIFs,eIF3 is the largest and less-known initiation factor due to its intrinsic complexity.Aberration in eIF3A,the largest subunit of eIF3,is known to contribute to carcinogenesis and protection against evolution into higher-grade malignancy,and the altered expression or mutation of eIF3A affects the responses of cancer patients to platinum-based chemotherapy.Besides its role in cancinogenesis,eIF3A is also implicated in fibrosis,and the agents inhibiting eIF3A delay the progression of this disorder.The dual roles of eIF3A in tumorigenesis are probably due to the regulation of translation of different mRNAs at different stages of tumor progression by eIF3A.In tum the encoded products serve as pro-tumor or anti-tumor proteins at different stages.