Stolovich Miri, Lerer Tal, Bolkier Yoav, Cohen Hannah, Meyuhas Oded
Department of Biochemistry, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
J Biol Chem. 2005 Feb 18;280(7):5336-42. doi: 10.1074/jbc.M412434200. Epub 2004 Nov 29.
TOP mRNAs are translationally controlled by mitogenic, growth, and nutritional stimuli through a 5'-terminal oligopyrimidine tract. Here we show that LiCl can alleviate the translational repression of these mRNAs when progression through the cell cycle is blocked at G(0), G(1)/S, or G(2)/M phases in different cell lines and by various physiological and chemical means. This derepressive effect of LiCl does not involve resumption of cell division. Unlike its efficient derepressive effect in mitotically arrested cells, LiCl alleviates inefficiently the repression of TOP mRNAs in amino acid-deprived cells and has no effect in lymphoblastoids whose TOP mRNAs are constitutively repressed even when they are proliferating. LiCl is widely used as a relatively selective inhibitor of glycogen synthase kinase-3. However, inhibition per se of this enzyme by more specific drugs failed to derepress the translation of TOP mRNAs, implying that relief of the translational repression of TOP mRNAs by LiCl is carried out in a glycogen synthase kinase-3-independent manner. Moreover, this effect is apparent, at least in some cell lines, in the absence of S6-kinase 1 activation and ribosomal protein S6 phosphorylation, thus further supporting the notion that translational control of TOP mRNAs does not rely on either of these variables.
顶端（TOP）mRNA通过5'-末端寡嘧啶序列受有丝分裂原、生长和营养刺激的翻译调控。我们在此表明，当不同细胞系通过各种生理和化学手段在G(0)、G(1)/S或G(2)/M期阻断细胞周期进程时，氯化锂（LiCl）可减轻这些mRNA的翻译抑制。LiCl的这种去抑制作用不涉及细胞分裂的恢复。与它在有丝分裂停滞细胞中的有效去抑制作用不同，LiCl在氨基酸缺乏的细胞中只能低效减轻TOP mRNA的抑制，并且对即使在增殖时其TOP mRNA也持续受到抑制的淋巴母细胞系没有作用。LiCl被广泛用作糖原合酶激酶-3相对选择性的抑制剂。然而，用更特异的药物单独抑制该酶并不能解除TOP mRNA的翻译抑制，这意味着LiCl对TOP mRNA翻译抑制的解除是以一种不依赖糖原合酶激酶-3的方式进行的。此外，至少在一些细胞系中，这种效应在没有S6激酶1激活和核糖体蛋白S6磷酸化的情况下也很明显，从而进一步支持了TOP mRNA的翻译调控不依赖于这些变量中的任何一个的观点。
