Aneugenic activity of Op18/stathmin is potentiated by the somatic Q18→E mutation in leukemic cells
Aneugenic activity of Op18/stathmin is potentiated by the somatic Q18→E mutation in leukemic cells
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DOI：
10.1091/mbc.e06-02-0165
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发表时间：
2006-07-01
影响因子：
3.3
通讯作者：
Gullberg, Martin
中科院分区：
文献类型：
--
作者：
Holmfeldt, Per;Brannstrom, Kristoffer;Gullberg, Martin
Op18/stathmin (Op18) 是一种磷酸化调节的微管去稳定剂，在肿瘤中经常过度表达。最近通过在腺癌中鉴定 Op18 的体细胞 Q18 -> E 突变，表明了 Op18 在恶性肿瘤中的重要性。我们通过分析 K562 细胞的细胞周期来解决白血病中 Op18 异常表达的功能后果，这些细胞要么通过表达干扰发夹 RNA 来耗尽 Op18，要么诱导表达野生型或 Q18E 取代的 Op18。我们在此表明，尽管 Op18 耗尽会增加间期微管密度，但有丝分裂纺锤体的密度基本上没有改变，细胞分裂正常。这与有丝分裂期间 Op18 的磷酸化失活一致。野生型 Op18 的过度表达会导致非整倍体活性，表现为异常的有丝分裂、多倍体化和染色体丢失。一项特别重要的发现是，Q18 -> E 突变显着增加了 Op18 的非整倍体活性。突变体 Op18 的过度活跃在其未磷酸化状态下是明显的，并且该突变还抑制 Op18 的微管不稳定活性的磷酸化失活，而对其磷酸化状态没有任何明显影响。因此，尽管 Op18 对于有丝分裂来说是可有可无的，但过度活跃的 Q18 -> E 突变体或过度表达的野生型 Op18 会产生非整倍体效应，可能导致肿瘤中的染色体不稳定。
Op18/stathmin (Op18) is a phosphorylation-regulated microtubule destabilizer that is frequently overexpressed in tumors. The importance of Op18 in malignancy was recently suggested by identification of a somatic Q18 -> E mutation of Op18 in an adenocarcinoma. We addressed the functional consequences of aberrant Op18 expression in leukemias by analyzing the cell cycle of K562 cells either depleted of Op18 by expression of interfering hairpin RNA or induced to express wild-type or Q18E substituted Op18. We show here that although Op18 depletion increases microtubule density during interphase, the density of mitotic spindles is essentially unaltered and cells divide normally. This is consistent with phosphorylation-inactivation of Op18 during mitosis. Overexpression of wild-type Op18 results in aneugenic activities, manifest as aberrant mitosis, polyploidization, and chromosome loss. One particularly significant finding was that the aneugenic activity of Op18 was dramatically increased by the Q18 -> E mutation. The hyperactivity of mutant Op18 is apparent in its unphosphorylated state, and this mutation also suppresses phosphorylation-inactivation of the microtubule-destabilizing activity of Op18 without any apparent effect on its phosphorylation status. Thus, although Op18 is dispensable for mitosis, the hyperactive Q18 -> E mutant, or overexpressed wild-type Op18, exerts aneugenic effects that are likely to contribute to chromosomal instability in tumors.