Partial downregulation of MAD1 causes spindle checkpoint inactivation and aneuploidy, but does not confer resistance towards taxol
Partial downregulation of MAD1 causes spindle checkpoint inactivation and aneuploidy, but does not confer resistance towards taxol
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DOI：
10.1038/sj.onc.1208589
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发表时间：
2005-06-16
期刊：
影响因子：
8
通讯作者：
Bastians, H
中科院分区：
文献类型：
--
作者：
Kienitz, A;Vogel, C;Bastians, H
有丝分裂纺锤体组装检查点通过抑制有丝分裂后期的开始，直到所有的动点都附着在有丝分裂的纺锤体上，并产生跨越动点的张力，来确保有丝分裂过程中适当的染色体分离。在这里，我们报告了在人类癌症中观察到的纺锤体检查点基因MAD1的稳定部分下调，导致纺锤体检查点功能失活，导致大体非整倍体。有趣的是，尽管MAD1被认为在检查点激活过程中作为MAD2的动粒激活器，但我们表明正常水平的MAD2，而不是MAD1，是防止过早的姐妹染色单体分离和维持未受干扰的有丝分裂的时间所必需的，这表明MAD2的MAD1独立功能独立于其检查点功能运行。最重要的是，对MAD1或MAD2的部分抑制会使人对诺康唑产生耐药性，诺可唑是一种抑制微管附着的药物。相比之下，对临床相关药物如紫杉醇或莫那曲尔的敏感性并不受MAD1部分下调的调节，这表明纺锤体检查点依赖的凋亡通路存在功能分歧。
The mitotic spindle assembly checkpoint ensures proper chromosome segregation during mitosis by inhibiting the onset of anaphase until all kinetochores are attached to the mitotic spindle and tension across the kinetochores is generated. Here, we report that the stable partial downregulation of the spindle checkpoint gene MAD1, which is observed in human cancer, leads to a functional inactivation of the spindle checkpoint resulting in gross aneuploidy. Interestingly, although Mad1 is thought to act as a kinetochore based activator of Mad2 during checkpoint activation, we show that normal levels of Mad2, but not of Mad1, are required for preventing premature sister chromatid separation and for maintaining the timing of an undisturbed mitosis, suggesting a Mad1 independent function of Mad2 that operates independent of its checkpoint function. Most significantly, a partial repression of either MAD1 or MAD2 confers resistance to nocodazole, a drug that inhibits microtubule attachment. In contrast, sensitivity to clinically relevant drugs like taxol or monastrol that inhibit the generation of tension across kinetochores is not modulated by partial downregulation of MAD1, suggesting a functional bifurcation of spindle checkpoint dependent apoptotic pathways.