Role of hypusinated eukaryotic translation initiation factor 5A in polyamine depletion-induced cytostasis
Role of hypusinated eukaryotic translation initiation factor 5A in polyamine depletion-induced cytostasis
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DOI：
10.1074/jbc.m704282200
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发表时间：
2007-11-30
影响因子：
4.8
通讯作者：
Janne, Juhani
中科院分区：
文献类型：
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作者：
Hyvonen, Mervi T.;Keinanen, Tuomo A.;Janne, Juhani
我们之前已经证明，α-甲基化亚精胺和精胺类似物可以将细胞从多胺耗尽引起的生长抑制中拯救出来，并在严重多胺缺乏的情况下维持胰腺的完整性。然而，由于 α-甲基亚精胺可以作为 hypusine 的前体，而 hypusine 是细胞增殖所需的功能性真核翻译起始因子 5A 的组成部分，并且由于 alpha,omega-双甲基精胺可以转化为甲基亚精胺，因此尚不完全清楚细胞生长的恢复是否实际上归因于由这些多胺类似物形成的 hypusine。在这里，我们使用了甲基化亚精胺和精胺的光学活性异构体，并表明，培养细胞中多胺耗竭诱导的急性细胞停滞可以被甲基多胺的所有异构体逆转，无论它们是否作为甲基多胺的前体。在具有激活的多胺分解代谢的转基因大鼠中，所有异构体类似地恢复了肝再生并降低了与诱发的胰腺炎相关的血浆α-淀粉酶活性。在上述实验条件下，双甲基精胺的(S，S)异构体而非(R，R)异构体明显通过精胺氧化酶的作用转化为甲基亚精胺，该酶强烈偏好(S，S)异构体。然而，在类似物中，只有 (S)-甲基亚精胺在长期（超过 1 周）多胺生物合成抑制期间维持细胞生长。它也是唯一能有效转化为马尿苷的异构体，表明脱氧马尿苷合酶同样具有隐藏的立体特异性。总而言之，结果表明，多胺消耗引起的生长抑制涉及两个阶段，即急性期和晚期乙型肝炎依赖期。
We have earlier shown that alpha-methylated spermidine and spermine analogues rescue cells from polyamine depletion-induced growth inhibition and maintain pancreatic integrity under severe polyamine deprivation. However, because alpha-methylspermidine can serve as a precursor of hypusine, an integral part of functional eukaryotic translation initiation factor 5A required for cell proliferation, and because alpha,omega-bismethylspermine can be converted to methylspermidine, it is not entirely clear whether the restoration of cell growth is actually attributable to hypusine formed from these polyamine analogues. Here, we have used optically active isomers of methylated spermidine and spermine and show that polyamine depletion-induced acute cytostasis in cultured cells could be reversed by all the isomers of the methylpolyamines irrespective of whether they served or not as precursors of hypusine. In transgenic rats with activated polyamine catabolism, all the isomers similarly restored liver regeneration and reduced plasma alpha-amylase activity associated with induced pancreatitis. Under the above experimental conditions, the (S,S)-but not the (R,R)-isomer of bismethylspermine was converted to methylspermidine apparently through the action of spermine oxidase strongly preferring the (S,S)-isomer. Of the analogues, however, only (S)-methylspermidine sustained cell growth during prolonged (more than 1 week) inhibition of polyamine biosynthesis. It was also the only isomer efficiently converted to hypusine, indicating that deoxyhypusine synthase likewise possesses hidden stereospecificity. Taken together, the results show that growth inhibition in response to polyamine depletion involves two phases, an acute and a late hypusine-dependent phase.