Stathmin inhibition enhances okadaic acid-induced mitotic arrest - A potential role for stathmin in mitotic exit
Stathmin inhibition enhances okadaic acid-induced mitotic arrest - A potential role for stathmin in mitotic exit
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DOI：
10.1074/jbc.m011654200
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发表时间：
2001-08-17
影响因子：
4.8
通讯作者：
Atweh, GF
中科院分区：
文献类型：
--
作者：
Mistry, SJ;Atweh, GF
Stathmin是一种微管不稳定的磷蛋白，在有丝分裂的调节中起着关键作用。在有丝分裂中，stathmin的微管解聚活性在磷酸化后丧失。尽管p34（cdc 2）激酶磷酸化stathmin在有丝分裂纺锤体组装中的作用已得到充分证实，但stathmin去磷酸化在有丝分裂中的作用尚不清楚。在这项研究中，我们测试的假设，stathmin的去磷酸化可能是至关重要的有丝分裂纺锤体的解聚和退出有丝分裂。我们比较了冈田酸，丝氨酸/苏氨酸蛋白磷酸酶的特异性抑制剂，在存在或不存在stathmin缺陷的有丝分裂进程的不同参数的影响。由于冈田酸阻止stathmin的去磷酸化并导致无活性磷酸化形式的积累，因此预期在存在相对stathmin缺乏的情况下，暴露于冈田酸对有丝分裂具有更深远的影响。我们发现，抑制stathmin表达的结果在增加的敏感性，冈田酸的抗有丝分裂作用。这反映在与有丝分裂阻滞相关的生长抑制增加。绝大多数的stathmin抑制细胞被发现被逮捕在后期中期/后期，并有严重的有丝分裂纺锤体异常。暴露于冈田酸也导致在stathmin抑制的细胞中聚合/未聚合的微管蛋白的比例相对于对照细胞更大。因为对照和stathmin抑制细胞之间的唯一差异是stathmin在后者中的缺乏，所以stathmin抑制细胞对冈田酸诱导的有丝分裂停滞的敏感性增加意味着stathmin在有丝分裂的后期阶段中的作用。
Stathmin is a microtubule-destabilizing phosphoprotein that plays a critical role in the regulation of mitosis. The microtubule-depolymerizing activity of stathmin is lost upon phosphorylation in mitosis. Although the role of phosphorylation of stathmin by p34(cdc2) kinase in the assembly of the mitotic spindle is well established, the role of dephosphorylation of stathmin in mitosis is unknown. In this study, we tested the hypothesis that dephosphorylation of stathmin may be critically important for the depolymerization of the mitotic spindle and the exit from mitosis. We compared the effects of okadaic acid, a specific inhibitor of serine/threonine protein phosphatases, on different parameters of mitotic progression in the presence or absence of stathmin deficiency. Because okadaic acid prevents dephosphorylation of stathmin and results in accumulation of the inactive phosphorylated form, exposure to okadaic acid would be expected to have a more profound effect on mitosis in the presence of relative stathmin deficiency. We found that inhibition of stathmin expression results in increased sensitivity to the antimitotic effects of okadaic acid. This was reflected by increased growth inhibition associated with mitotic arrest. A vast majority of the stathmin-inhibited cells were found to be arrested in late metaphase/anaphase and had severe mitotic spindle abnormalities. Exposure to okadaic acid also resulted in a bigger ratio of polymerized/unpolymerized tubulin in stathmin-inhibited cells relative to control cells. Because the only difference between the control and the stathmin-inhibited cells is the deficiency of stathmin in the latter, the increased susceptibility of the stathmin-inhibited cells to okadaic acid-induced mitotic arrest implies a role for stathmin in the later stages of mitosis.