eIF4GI links nutrient sensing by mTOR to cell proliferation and inhibition of autophagy.
eIF4GI links nutrient sensing by mTOR to cell proliferation and inhibition of autophagy.
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DOI：
10.1083/jcb.200710215
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发表时间：
2008-04-21
期刊：
影响因子：
--
通讯作者：
Schneider RJ
中科院分区：
文献类型：
--
作者：
Ramírez-Valle F;Braunstein S;Zavadil J;Formenti SC;Schneider RJ
翻译启动因子在细胞中具有复杂的功能，目前尚不清楚。我们发现，启动因子eIF4GI的缺失只会适度减少细胞中的整体蛋白质合成，但会导致营养饥饿或抑制关键的营养传感器蛋白激酶mTOR。EIF4GI缺失会损害细胞增殖、生物能量学和线粒体活性，从而促进自噬。参与细胞生长、增殖和生物能量学的mRNAs的翻译被eIF4GI选择性地抑制，编码抑制p27的Skp2的mRNA也是如此，而分解代谢途径因子则增加。其他eIF4G家族成员的缺失或过度表达并不能概括这些结果。由于存在多个上游开放阅读框和较低的mRNA丰度，大多数eIF4GI缺失的翻译受损的mRNAs被排除在多聚核糖体之外。这些结果表明，在许多乳腺癌中观察到的高水平的eIF4GI可能特定地促进了增殖，防止了自噬，并通过营养感应释放了肿瘤细胞。
Translation initiation factors have complex functions in cells that are not yet understood. We show that depletion of initiation factor eIF4GI only modestly reduces overall protein synthesis in cells, but phenocopies nutrient starvation or inhibition of protein kinase mTOR, a key nutrient sensor. eIF4GI depletion impairs cell proliferation, bioenergetics, and mitochondrial activity, thereby promoting autophagy. Translation of mRNAs involved in cell growth, proliferation, and bioenergetics were selectively inhibited by reduction of eIF4GI, as was the mRNA encoding Skp2 that inhibits p27, whereas catabolic pathway factors were increased. Depletion or overexpression of other eIF4G family members did not recapitulate these results. The majority of mRNAs that were translationally impaired with eIF4GI depletion were excluded from polyribosomes due to the presence of multiple upstream open reading frames and low mRNA abundance. These results suggest that the high levels of eIF4GI observed in many breast cancers might act to specifically increase proliferation, prevent autophagy, and release tumor cells from control by nutrient sensing.
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