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Cell Cycle Progression and Proliferation Despite 4BP-1 Dephosphorylation

机译：尽管4BP-1去磷酸化，细胞周期进程和增殖

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摘要

Proliferation and cell cycle progression in response to growth factors require de novo protein synthesis. It has been proposed that binding of the eukaryotic translation initiation factor 4E (eIF-4E) to the inhibitory protein 4BP-1 blocks translation by preventing access of eIF-4G to the 5′ cap of the mRNA. The signal for translation initiation is thought to involve phosphorylation of 4BP-1, which causes it to dissociate from eIF-4E and allows eIF-4G to localize to the 5′ cap. It has been suggested that the ability of the macrolide antibiotic rapamycin to inhibit 4BP-1 phosphorylation is responsible for the potent antiproliferative property of this drug. We now show that rapamycin-resistant cells exhibited normal proliferation despite dephosphorylation of 4BP-1 that allows it to bind to eIF-4E. Moreover, despite rapamycin-induced dephosphorylation of 4BP-1, eIF-4E–eIF-4G complexes (eIF-4F) were still detected. In contrast, amino acid withdrawal, which caused a similar degree of 4BP-1 dephosphorylation, resulted in dissociation of the eIF-4E–eIF-4G complex. Thus, 4BP-1 dephosphorylation is not equivalent to eIF-4E inactivation and does not explain the antiproliferative property of rapamycin.
机译：响应生长因子的增殖和细胞周期进程需要从头进行蛋白质合成。已经提出，真核翻译起始因子4E（eIF-4E）与抑制蛋白4BP-1的结合通过阻止eIF-4G接近mRNA的5'帽来阻止翻译。据认为，用于翻译起始的信号涉及4BP-1的磷酸化，这导致其与eIF-4E分离并允许eIF-4G定位于5'帽。已经表明，大环内酯类抗生素雷帕霉素抑制4BP-1磷酸化的能力是该药物有效的抗增殖特性。我们现在显示，尽管4BP-1的去磷酸化使雷帕霉素抗性细胞能够结合到eIF-4E，但仍显示出正常的增殖。此外，尽管雷帕霉素诱导了4BP-1的去磷酸化，但仍检测到eIF-4E–eIF-4G复合物（eIF-4F）。相比之下，氨基酸撤离引起相似程度的4BP-1去磷酸化，导致eIF-4E–eIF-4G复合物解离。因此，4BP-1去磷酸化不等同于eIF-4E的失活，并且不能解释雷帕霉素的抗增殖特性。

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