MAP Kinase Regulation of the Mitotic Spindle Checkpoint
MAP Kinase Regulation of the Mitotic Spindle Checkpoint
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DOI：
10.1007/978-1-60761-795-2_31
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发表时间：
2010-01-01
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影响因子：
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通讯作者：
Rosner, Marsha Rich
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文献类型：
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作者：
Eves, Eva M.;Rosner, Marsha Rich
维持细胞周期的完整性对于确保细胞仅在受控条件下响应离散刺激进行 DNA 复制和增殖至关重要。保证该过程保真度的一种机制是通过细胞周期检查点的激活。有丝分裂纺锤体检查点由 Aurora B 激酶调节，确保动粒正确附着在染色体上，从而使染色体均匀分布到子细胞。我们证明丝裂原激活蛋白激酶（MAPK）级联调节有丝分裂进展和纺锤体检查点。正如着丝粒免疫荧光所示，Raf 激酶抑制蛋白 (RKIP)（Raf/MEK/ERK 信号传导抑制剂）的耗竭会导致 MAPK 活性增加，从而抑制 Aurora B 激酶活性。通过监测有丝分裂指数和从核膜破裂到后期的转运时间，我们证明 RKIP 耗尽会导致纺锤体检查点缺陷和基因组不稳定，特别是对破坏微管功能的药物的反应。
Maintaining the integrity of the cell cycle is critical for ensuring that cells only undergo DNA replication and proliferation under controlled conditions in response to discrete stimuli. One mechanism by which the fidelity of this process is guaranteed is through the activation of cell cycle checkpoints. The mitotic spindle checkpoint, which is regulated by Aurora B kinase, ensures proper kinetochore attachment to chromosomes leading to equal distribution of chromosomes to daughter cells. We demonstrated that the mitogen-activated protein kinase (MAPK) cascade regulates mitotic progression and the spindle checkpoint. As demonstrated by immunofluorescence at kinetochores, depletion of Raf Kinase Inhibitory Protein (RKIP), an inhibitor of Raf/MEK/ERK signaling, causes an increase in MAPK activity that inhibits Aurora B kinase activity. By monitoring mitotic index and transit time from nuclear envelope breakdown to anaphase, we demonstrated that RKIP depletion leads to a defective spindle checkpoint and genomic instability, particularly in response to drugs that disrupt microtubule function.