The Tuberin and Cyclin B1 complex functions as a novel G2/M sensor of serum conditions and Akt signaling
The Tuberin and Cyclin B1 complex functions as a novel G2/M sensor of serum conditions and Akt signaling
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DOI：
10.1371/journal.pone.0210612
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发表时间：
2019-01-10
期刊：
影响因子：
3.7
通讯作者：
Porter, Lisa A.
中科院分区：
文献类型：
--
作者：
da Silva, Elizabeth Fidalgo;Botsford, Sabrina;Porter, Lisa A.
大量开创性的工作已经确定，Tuberin和Hamartin复合体通过G1/S作为蛋白质合成和细胞周期进展的负调控因子发挥作用，这在很大程度上归因于Tuberin的GTPase活性间接抑制哺乳动物的雷帕霉素靶标(MTOR)。在营养充足的时候，Tuberin被生长因子信号抑制，包括Akt/PKB的直接磷酸化，允许激活mTOR和随后的蛋白质合成。维持动态平衡需要细胞生长(mTOR信号)和细胞分裂(细胞周期调节)之间的联系，这是很合理的，然而这是如何发生的机制尚未解决。这项工作表明，在高血清和/或Akt信号存在的情况下，Tuberin与G2/M期细胞周期蛋白Cyclin B1的直接结合稳定，有丝分裂进入率降低。重要的是，我们发现这会导致细胞大小的增加。我们认为，这代表了一个新的细胞周期检查点，将有丝分裂的开始与细胞的营养状态联系起来，以控制细胞生长。
A great deal of ground breaking work has determined that the Tuberin and Hamartin Complex function as a negative regulator of protein synthesis and cell cycle progression through G1/S. This is largely attributed to the GTPase activity of Tuberin that indirectly inhibits the mammalian target of rapamycin (mTOR). During times of ample nutrition Tuberin is inhibited by growth factor signaling, including direct phosphorylation by Akt/PKB, allowing for activation of mTOR and subsequent protein synthesis. It is well rationalized that maintaining homeostasis requires communication between cell growth (mTOR signaling) and cell division (cell cycle regulation), however how this occurs mechanistically has not been resolved. This work demonstrates that in the presence of high serum, and/or Akt signaling, direct binding between Tuberin and the G2/M cyclin, Cyclin B1, is stabilized and the rate of mitotic entry is decreased. Importantly, we show that this results in an increase in cell size. We propose that this represents a novel cell cycle checkpoint linking mitotic onset with the nutritional status of the cell to control cell growth.