Raf kinase inhibitory protein regulates Aurora B kinase and the spindle checkpoint
Raf kinase inhibitory protein regulates Aurora B kinase and the spindle checkpoint
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DOI：
10.1016/j.molcel.2006.07.015
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发表时间：
2006-08-18
期刊：
影响因子：
16
通讯作者：
Rich Rosner, Marsha
中科院分区：
文献类型：
--
作者：
Eves, Eva M.;Shapiro, Paul;Rich Rosner, Marsha
Raf激酶抑制蛋白（RKIP或PEBP）是Raf/MEK/MAP激酶信号级联的抑制剂和癌症转移的抑制剂。我们现在表明，RKIP协会与中心体和动粒和调节纺锤体检查点在哺乳动物细胞。RKIP耗竭导致有丝分裂指数、中期细胞数量和从核膜破裂到后期的穿越时间减少，以及纺锤体毒物诱导的有丝分裂检查点被覆盖。Raf-1耗竭或MEK抑制逆转有丝分裂指数的降低，而Raf的超活化模拟RKIP耗竭表型。最后，RKIP耗竭或Raf超活化降低了着丝粒定位和Aurora B的激酶活性，Aurora B是纺锤体检查点的调节剂。这些结果表明，RKIP通过Raf-1/MEK/ERK级联调节极光B激酶和纺锤体检查点，并证明MAP激酶（MAPK）通路的微小变化可以深刻影响细胞周期的保真度。
Raf kinase inhibitory protein (RKIP or PEBP) is an inhibitor of the Raf/MEK/MAP kinase signaling cascade and a suppressor of cancer metastasis. We now show that RKIP associates with centrosomes and kinetochores and regulates the spindle checkpoint in mammalian cells. RKIP depletion causes decreases in the mitotic index, the number of metaphase cells, and traversal times from nuclear envelope breakdown to anaphase, and an override of mitotic checkpoints induced by spindle poisons. Raf-1 depletion or MEK inhibition reverses the reduction in the mitotic index, whereas hyperactivation of Raf mimics the RKIP-depletion phenotype. Finally, RKIP depletion or Raf hyperactivation reduces kinetochore localization and kinase activity of Aurora B, a regulator of the spindle checkpoint. These results indicate that RKIP regulates Aurora B kinase and the spindle checkpoint via the Raf-1/MEK/ERK cascade and demonstrate that small changes in the MAP kinase (MAPK) pathway can profoundly impact the fidelity of the cell cycle.