Eves Eva M, Shapiro Paul, Naik Karuna, Klein Ulf R, Trakul Nicholas, Rosner Marsha Rich
Ben May Institute for Cancer Research, University of Chicago, Chicago, Illinois 60637, USA.
Mol Cell. 2006 Aug;23(4):561-74. doi: 10.1016/j.molcel.2006.07.015.
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.
Raf激酶抑制蛋白（RKIP或PEBP）是Raf/MEK/MAP激酶信号级联反应的抑制剂，也是癌症转移的抑制因子。我们现在发现，RKIP与中心体和动粒相关，并在哺乳动物细胞中调节纺锤体检查点。RKIP缺失会导致有丝分裂指数、中期细胞数量以及从核膜破裂到后期的穿越时间减少，并使纺锤体毒素诱导的有丝分裂检查点失效。Raf-1缺失或MEK抑制可逆转有丝分裂指数的降低，而Raf的过度激活则模拟了RKIP缺失的表型。最后，RKIP缺失或Raf过度激活会降低纺锤体检查点调节因子Aurora B的动粒定位和激酶活性。这些结果表明，RKIP通过Raf-1/MEK/ERK级联反应调节Aurora B激酶和纺锤体检查点，并证明MAP激酶（MAPK）途径的微小变化可深刻影响细胞周期的保真度。
