Eukaryotic initiation factor 6 is rate-limiting in translation, growth and transformation.
Eukaryotic initiation factor 6 is rate-limiting in translation, growth and transformation.
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DOI：
10.1038/nature07267
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发表时间：
2008-10-02
期刊：
影响因子：
64.8
通讯作者：
Biffo, Stefano
中科院分区：
文献类型：
--
作者：
Gandin, Valentina;Miluzio, Annarita;Barbieri, Anna Maria;Beugnet, Anne;Kiyokawa, Hiroaki;Marchisio, Pier Carlo;Biffo, Stefano
细胞生长和增殖需要协调的核糖体生物发生和翻译。真核起始因子（Eukaryotic Initiation Factors, eIF）在起始的限速阶段控制翻译。到目前为止，只有两个eif将细胞外刺激与整体翻译速率联系起来；eIF4E在eIF4F复合体中起作用，调节被封顶mRNA与生长因子下游40S亚基的结合；eIF2控制40S亚基上三元复合物的负载，并在应激刺激下被抑制。没有发现eif将细胞外刺激与大60S核糖体亚基的活性联系起来。eIF6结合60S核糖体，阻止核糖体在体外结合。然而，对酵母的研究表明，eIF6是核糖体生物发生所必需的，而不是翻译所必需的。我们发现，在体内，哺乳动物的eIF6是有效启动翻译所必需的。eIF6阴性胚胎在着床前是致命的。杂合小鼠在所有组织中eIF6水平降低50%，由于细胞数量减少和G1/S细胞周期进程受损，肝脏和脂肪组织的质量减少。eIF6+/−细胞保留足够的核仁eIF6和正常的核糖体生物发生。eIF6+/−小鼠的肝脏在多染色体谱中显示80S增加，表明翻译起始缺陷。一致地，分离的肝细胞受损胰岛素刺激的翻译。杂合子小鼠胚胎成纤维细胞（mef）具有生物体表型，核糖体生物发生正常，胰岛素刺激的翻译减少，G1/S期进展延迟。此外，eIF6+/−细胞抵抗癌基因诱导的转化。因此，eIF6是第一个与响应胞外信号调节翻译的60S大亚基相关的eIF。
Cell growth and proliferation require coordinated ribosomal biogenesis and translation. Eukaryotic Initiation Factors (eIF) control translation at the rate-limiting step of initiation. So far, only two eIFs connect extracellular stimuli to global translation rates; eIF4E acts in the eIF4F complex and regulates binding of capped mRNA to 40S subunits, downstream of growth factors; eIF2 controls loading of the ternary complex on the 40S subunit and is inhibited upon stress stimuli. No eIFs have been found to link extracellular stimuli to the activity of the large 60S ribosomal subunit. eIF6 binds 60S ribosomes precluding ribosome joining in vitro. However studies in yeasts showed that eIF6 is required for ribosome biogenesis rather than translation. We show that mammalian eIF6 is required for efficient initiation of translation, in vivo. eIF6 null embryos are lethal at preimplantation. Heterozygous mice have 50% reduction of eIF6 levels in all tissues, and show reduced mass of hepatic and adipose tissues due to a lower number of cells and to impaired G1/S cell cycle progression. eIF6+/− cells retain sufficient nucleolar eIF6 and normal ribosome biogenesis. The liver of eIF6+/− mice displays an increase of 80S in polysomal profiles, indicating a defect in initiation of translation. Consistently, isolated hepatocytes have impaired insulin-stimulated translation. Heterozygous mouse embryonic fibroblasts (MEFs) recapitulate the organism phenotype and have normal ribosome biogenesis, reduced insulin-stimulated translation, and delayed G1/S phase progression. Furthermore, eIF6+/− cells resist to oncogene-induced transformation. Thus, eIF6 is the first eIF associated with the large 60S subunit that regulates translation in response to extracellular signals.
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影响因子：
21.3
作者：
Colombo, E;Marine, JC;Pelicci, PG
通讯作者：
Pelicci, PG
DOI：
10.1073/pnas.0409513102
发表时间：
2005-06-28
影响因子：
11.1
作者：
Gorrini, C;Loreni, F;Biffo, S
通讯作者：
Biffo, S
DOI：
10.1083/jcb.144.5.823
发表时间：
1999-03-08
期刊：
The Journal of cell biology
影响因子：
--
作者：
Sanvito F;Piatti S;Villa A;Bossi M;Lucchini G;Marchisio PC;Biffo S
通讯作者：
Biffo S
影响因子：
4.1
作者：
CLARK, RL;HANSEN, RJ
通讯作者：
HANSEN, RJ
影响因子：
4.8
作者：
Rim, JS;Mynatt, RL;Gawronska-Kozak, B
通讯作者：
Gawronska-Kozak, B