Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China.
Cell Biol Int. 2014 Jun;38(6):737-46. doi: 10.1002/cbin.10259. Epub 2014 Mar 18.
Microtubule interfering agents (MIAs), that can stabilise or depolymerise microtubules, are an important class of cancer chemotherapeutic drugs. They can lead to mitotic arrest and subsequent apoptosis. We demonstrate that cell cycle-dependent kinase 1 (CDK1) is important in switching cells from mitotic arrest to apoptosis during MIAs treatment. Overexpression of non-degradable cyclin B1 sustained CDK1 activation and mitotic arrest, followed by caspase-3 dependent apoptosis. CDK1 is responsible for the phosphorylation of several pro- and anti-apoptotic Bcl-2 family proteins during MIAs treatment. CDK1-mediated Bcl-2 serine 70 phosphorylation enhances its pro-apoptotic function, whereas CDK1-mediated Bad serine 128 phosphorylation promotes apoptosis. Blockage of CDK1 activity with a specific pharmacological inhibitor suppresses Mcl-1 phosphorylation, degradation and its anti-apoptotic function. Therefore, the death of cancer cells under MIAs treatment was caused by imbalance between CDK1-induced alterations in the pro-apoptotic and anti-apoptotic functions of phosphorylated Bcl-2 family proteins.
微管干扰剂（MIAs）可以稳定或解聚微管，是一类重要的癌症化疗药物。它们可以导致有丝分裂停滞和随后的细胞凋亡。我们证明，细胞周期依赖性激酶 1（CDK1）在 MIAs 治疗过程中，将细胞从有丝分裂阻滞切换到细胞凋亡中起着重要作用。不降解的 cyclin B1 的过表达维持 CDK1 的激活和有丝分裂阻滞，随后是 caspase-3 依赖性细胞凋亡。CDK1 负责在 MIAs 治疗过程中磷酸化几种促凋亡和抗凋亡 Bcl-2 家族蛋白。CDK1 介导的 Bcl-2 丝氨酸 70 磷酸化增强了其促凋亡功能，而 CDK1 介导的 Bad 丝氨酸 128 磷酸化促进细胞凋亡。用特异性药理学抑制剂阻断 CDK1 活性可抑制 Mcl-1 的磷酸化、降解及其抗凋亡功能。因此，在 MIAs 治疗下癌细胞的死亡是由 CDK1 诱导的磷酸化 Bcl-2 家族蛋白的促凋亡和抗凋亡功能改变之间的失衡引起的。
