EMI1 switches from being a substrate to an inhibitor of APC/C(CDH1) to start the cell cycle.
EMI1 switches from being a substrate to an inhibitor of APC/C(CDH1) to start the cell cycle.
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DOI：
10.1038/s41586-018-0199-7
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发表时间：
2018-06
期刊：
影响因子：
64.8
通讯作者：
Meyer T
中科院分区：
文献类型：
--
作者：
Cappell SD;Mark KG;Garbett D;Pack LR;Rape M;Meyer T
哺乳动物细胞在G1期结束前整合有丝分裂原和应激信号来决定是否进入细胞周期。细胞必须激活细胞周期蛋白依赖性激酶(CDKs)，诱导E2F转录程序，失活E3泛素连接酶，后期促进复合体/环体(Apc/CCdh1)，然后才能在S期复制自己的DNA。最近的研究表明，应激可以在CDK2激活和E2F诱导后使细胞恢复静止，但在APC/CCdh1失活后不能，认为APC/CCdh1失活是细胞周期进入的不返回点。虽然APC/CCdh1的快速失活需要早期有丝分裂抑制物1(Emi1)，但控制这一细胞周期承诺步骤的分子机制尚不清楚。在这里，我们证明了细胞周期承诺是由Emi1-APC/CCdh1双重负反馈开关介导的，其中Emi1既是APC/CCdh1的底物又是抑制物。失活开关触发在G1期间具有低Emi1水平和高APC/CCdh1活性的状态到在S和G2期间具有高Emi1水平和低APC/CCdh1活性的状态之间的转换。基于细胞的分析、体外重建和建模数据表明，潜在的双负反馈是双稳态的，代表了一种健壮的不可逆开关。综上所述，我们的研究认为，哺乳动物细胞通过增加CDK2活性和Emi1 mRNA的表达来触发单向APC/CCdh1失活开关，从而致力于细胞周期，该开关是由Emi1从APC/CCdh1的底物转变为APC/CCdh1的抑制因子。
Mammalian cells integrate mitogen and stress signaling prior to the end of G1 phase to decide whether or not to enter the cell cycle. Before cells can replicate their DNA in S phase, they have to activate cyclin-dependent kinases (CDKs), induce an E2F transcription program, and inactivate an E3 ubiquitin ligase, the anaphase promoting complex/cyclosome (APC/CCdh1). It was recently shown that stress can return cells to quiescence after CDK2 activation and E2F induction but cannot after inactivation of APC/CCdh1, arguing that APC/CCdh1 inactivation is the point-of-no-return for cell cycle entry. While rapid inactivation of APC/CCdh1 requires early mitotic inhibitor 1 (Emi1), the molecular mechanism controlling this cell cycle commitment step is unknown. Here we show that cell cycle commitment is mediated by an Emi1-APC/CCdh1 dual-negative feedback switch, in which Emi1 is both a substrate and an inhibitor of APC/CCdh1. The inactivation switch triggers a transition between a state with low Emi1 levels and high APC/CCdh1 activity during G1 to a state with high Emi1 levels and low APC/CCdh1 activity during S and G2. Cell-based analysis, in vitro reconstitution, and modeling data show that the underlying dual-negative feedback is bistable and represents a robust irreversible switch. Together, our study argues that mammalian cells commit to the cell cycle by increasing CDK2 activity and Emi1 mRNA expression to trigger a one-way APC/CCdh1 inactivation switch mediated by Emi1 transitioning from a substrate to an inhibitor of APC/CCdh1.
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影响因子：
64.8
作者：
通讯作者：
--
影响因子：
21.3
作者：
通讯作者：
--
影响因子：
8.8
作者：
Fukushima H;Ogura K;Wan L;Lu Y;Li V;Gao D;Liu P;Lau AW;Wu T;Kirschner MW;Inuzuka H;Wei W
通讯作者：
Wei W
影响因子：
64.8
作者：
Yang HW;Chung M;Kudo T;Meyer T
通讯作者：
Meyer T
DOI：
10.1083/jcb.200309035
发表时间：
2004-01-19
期刊：
The Journal of cell biology
影响因子：
--
作者：
Lindon C;Pines J
通讯作者：
Pines J