Dipartimento di Biotecnologie e Bioscienze, Università degli Studi di Milano-Bicocca, 20126 Milano, Italy.
J Cell Biol. 2010 Nov 29;191(5):981-97. doi: 10.1083/jcb.201007025. Epub 2010 Nov 22.
Upon prolonged activation of the spindle assembly checkpoint, cells escape from mitosis through a mechanism called adaptation or mitotic slippage, which is thought to underlie the resistance of cancer cells to antimitotic drugs. We show that, in budding yeast, this mechanism depends on known essential and nonessential regulators of mitotic exit, such as the Cdc14 early anaphase release (FEAR) pathway for the release of the Cdc14 phosphatase from the nucleolus in early anaphase. Moreover, the RSC (remodel the structure of chromatin) chromatin-remodeling complex bound to its accessory subunit Rsc2 is involved in this process as a novel component of the FEAR pathway. We show that Rsc2 interacts physically with the polo kinase Cdc5 and is required for timely phosphorylation of the Cdc14 inhibitor Net1, which is important to free Cdc14 in the active form. Our data suggest that fine-tuning regulators of mitotic exit have important functions during mitotic progression in cells treated with microtubule poisons and might be promising targets for cancer treatment.
当纺锤体组装检查点被长时间激活时，细胞会通过一种称为适应性或有丝分裂滑溜的机制逃避有丝分裂，据认为这种机制是癌细胞对抗有丝分裂药物产生耐药性的基础。我们表明，在芽殖酵母中，这种机制依赖于已知的有丝分裂退出的必需和非必需调节剂，例如 Cdc14 早期后期释放（FEAR）途径，用于在早期后期将 Cdc14 磷酸酶从核仁中释放出来。此外，与辅助亚基 Rsc2 结合的 RSC（重塑染色质结构）染色质重塑复合物作为 FEAR 途径的一个新组成部分参与了这个过程。我们表明，Rsc2 与 polo 激酶 Cdc5 物理相互作用，并且对于及时磷酸化 Cdc14 抑制剂 Net1 是必需的，这对于以活性形式释放 Cdc14 很重要。我们的数据表明，在使用微管毒素处理的细胞中，有丝分裂退出调节剂的精细调控在有丝分裂进程中具有重要功能，可能是癌症治疗的有前途的靶点。
