Amino acids and mTOR mediate distinct metabolic checkpoints in mammalian G1 cell cycle.
Amino acids and mTOR mediate distinct metabolic checkpoints in mammalian G1 cell cycle.
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DOI：
10.1371/journal.pone.0074157
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Foster DA
中科院分区：
文献类型：
--
作者：
Saqcena M;Menon D;Patel D;Mukhopadhyay S;Chow V;Foster DA
在多细胞生物中，细胞分裂受生长因子（GF）调节。在没有GF的情况下，细胞在G1中被称为限制点（R）的位点退出细胞周期，并进入被称为G 0的静止状态。此外，营养物质的可利用性影响G1细胞周期进程。虽然有大量关于G1细胞周期进展的文献，但仍然存在混乱-特别是关于R相对于营养介导的检查点的时间位置。在这份报告中，我们研究了R和一系列代谢细胞周期检查点之间的关系，调节进入S期。我们使用双区组实验对G1检查点进行排序，这些检查点监测GF、必需氨基酸（EEAs）、条件必需氨基酸谷氨酰胺和mTOR抑制的存在。细胞周期进程通过[3 H]-胸苷摄取和流式细胞术监测，细胞周期调控蛋白通过Western-blot分析。我们在这里报告说，GF介导的R可以在时间上区别于一系列晚期G1代谢检查点介导的EAA，谷氨酰胺，和mTOR -哺乳动物/机械雷帕霉素的目标。R明显位于EAA检查点的上游，EAA检查点位于谷氨酰胺检查点的上游。mTOR位于两个氨基酸检查点的下游，靠近S期。值得注意的是，除了GF自主性，我们发现人类癌细胞也有失调的代谢检查点。这里提供的数据与GF依赖性中期G1 R一致，其中细胞确定是否适合分裂，随后是一系列由氨基酸和mTOR介导的晚期G1代谢检查点，其中细胞确定它们是否具有足够的营养来完成任务。由于mTOR抑制在G1期最晚逮捕细胞，因此它可能是在致力于复制基因组之前营养充足的最终仲裁者。
In multicellular organisms, cell division is regulated by growth factors (GFs). In the absence of GFs, cells exit the cell cycle at a site in G1 referred to as the restriction point (R) and enter a state of quiescence known as G0. Additionally, nutrient availability impacts on G1 cell cycle progression. While there is a vast literature on G1 cell cycle progression, confusion remains – especially with regard to the temporal location of R relative to nutrient-mediated checkpoints. In this report, we have investigated the relationship between R and a series of metabolic cell cycle checkpoints that regulate passage into S-phase. We used double-block experiments to order G1 checkpoints that monitor the presence of GFs, essential amino acids (EEAs), the conditionally essential amino acid glutamine, and inhibition of mTOR. Cell cycle progression was monitored by uptake of [3H]-thymidine and flow cytometry, and analysis of cell cycle regulatory proteins was by Western-blot. We report here that the GF-mediated R can be temporally distinguished from a series of late G1 metabolic checkpoints mediated by EAAs, glutamine, and mTOR – the mammalian/mechanistic target of rapamycin. R is clearly upstream from an EAA checkpoint, which is upstream from a glutamine checkpoint. mTOR is downstream from both the amino acid checkpoints, close to S-phase. Significantly, in addition to GF autonomy, we find human cancer cells also have dysregulated metabolic checkpoints. The data provided here are consistent with a GF-dependent mid-G1 R where cells determine whether it is appropriate to divide, followed by a series of late-G1 metabolic checkpoints mediated by amino acids and mTOR where cells determine whether they have sufficient nutrients to accomplish the task. Since mTOR inhibition arrests cells the latest in G1, it is likely the final arbiter for nutrient sufficiency prior to committing to replicating the genome.
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影响因子：
10.5
作者：
LaBaer, J;Garrett, MD;Harlow, E
通讯作者：
Harlow, E
影响因子：
13.5
作者：
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通讯作者：
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DOI：
10.18632/aging.100422
发表时间：
2011-12
期刊：
Aging
影响因子：
--
作者：
Blagosklonny MV
通讯作者：
Blagosklonny MV
影响因子：
4.8
作者：
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通讯作者：
Ohsumi, Y
影响因子：
8.8
作者：
Platz, A;Sevigny, P;Norberg, T;Ring, P;Lagerlof, B;Ringborg, U
通讯作者：
Ringborg, U