Altered G1 signaling order and commitment point in cells proliferating without CDK4/6 activity.
Altered G1 signaling order and commitment point in cells proliferating without CDK4/6 activity.
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DOI：
10.1038/s41467-020-18966-9
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发表时间：
2020-10-20
影响因子：
16.6
通讯作者：
Meyer T
中科院分区：
文献类型：
--
作者：
Liu C;Konagaya Y;Chung M;Daigh LH;Fan Y;Yang HW;Terai K;Matsuda M;Meyer T
细胞周期的进入依赖于信号事件的有序进展。首先，细胞首先激活激酶细胞周期蛋白D-CDK 4/6，这导致视网膜母细胞瘤蛋白Rb的最终失活。几小时后，细胞聚集在APC/CCDH 1上，并穿过最终的承诺点。然而，许多具有基因缺失的细胞周期蛋白Ds的细胞可以补偿和增殖，所述细胞周期蛋白Ds激活并赋予CDK 4/6特异性。尽管它在癌症中很重要，但这种进入机制如何运作仍然缺乏特征，细胞在正常条件下是否使用这条路径仍然未知。在这里，使用单细胞显微镜，我们证明了细胞与急性抑制CDK 4/6进入细胞周期与缓慢和波动的细胞周期蛋白E-CDK 2活性增加。令人惊讶的是，在低CDK 4/6活性的情况下，APC/CCDH 1和Rb失活的顺序在细胞系和野生型小鼠中都被逆转。最后，我们表明，作为这种信号转导的结果，Rb失活取代APC/CCDH 1失活的不归点。总之，我们阐明的分子步骤，使细胞周期进入没有CDK 4/6活性。我们的研究结果不仅在癌症抗性方面有意义，而且还揭示了G1调节回路的时间可塑性。正常细胞如何在没有CDK 4和CDK 6（两种癌症驱动激酶）的情况下增殖仍不清楚。在这里，作者表明，没有CDK 4/6活性，细胞以不同的信号顺序和承诺点启动细胞周期，揭示了细胞周期进入机制的意外灵活性。
Cell-cycle entry relies on an orderly progression of signaling events. To start, cells first activate the kinase cyclin D-CDK4/6, which leads to eventual inactivation of the retinoblastoma protein Rb. Hours later, cells inactivate APC/CCDH1 and cross the final commitment point. However, many cells with genetically deleted cyclin Ds, which activate and confer specificity to CDK4/6, can compensate and proliferate. Despite its importance in cancer, how this entry mechanism operates remains poorly characterized, and whether cells use this path under normal conditions remains unknown. Here, using single-cell microscopy, we demonstrate that cells with acutely inhibited CDK4/6 enter the cell cycle with a slowed and fluctuating cyclin E-CDK2 activity increase. Surprisingly, with low CDK4/6 activity, the order of APC/CCDH1 and Rb inactivation is reversed in both cell lines and wild-type mice. Finally, we show that as a consequence of this signaling inversion, Rb inactivation replaces APC/CCDH1 inactivation as the point of no return. Together, we elucidate the molecular steps that enable cell-cycle entry without CDK4/6 activity. Our findings not only have implications in cancer resistance, but also reveal temporal plasticity underlying the G1 regulatory circuit. How normal cells proliferate without CDK4 and CDK6, two cancer-driving kinases, remains unclear. Here, the authors show that without CDK4/6 activity, cells start the cell cycle with a different signaling order and commitment point, revealing unexpected flexibility in cell-cycle entry mechanisms.
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影响因子：
64.8
作者：
Cappell SD;Mark KG;Garbett D;Pack LR;Rape M;Meyer T
通讯作者：
Meyer T
影响因子：
9.3
作者：
Barr AR;Heldt FS;Zhang T;Bakal C;Novák B
通讯作者：
Novák B
影响因子：
8
作者：
Dean, J. L.;Thangavel, C.;Knudsen, E. S.
通讯作者：
Knudsen, E. S.
影响因子：
64.5
作者：
ELDEIRY, WS;TOKINO, T;VOGELSTEIN, B
通讯作者：
VOGELSTEIN, B
DOI：
10.4161/cc.8.7.8042
发表时间：
2009-04-01
期刊：
Cell cycle (Georgetown, Tex.)
影响因子：
--
作者：
Hahn AT;Jones JT;Meyer T
通讯作者：
Meyer T