Fu Xu-feng, Yao Kun, Du Xing, Li Yan, Yang Xiu-yu, Yu Min, Li Mei-zhang, Cui Qing-hua
School of Life Sciences, Yunnan University, Kunming 650091, China.
School of Medicine, Yunnan University, Kunming 650091, China.
J Zhejiang Univ Sci B. 2016 Feb;17(2):136-46. doi: 10.1631/jzus.B1500158.
Peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) is a transcriptional co-activator involved in mitochondrial biogenesis, respiratory capacity, and oxidative phosphorylation (OXPHOS). PGC-1α plays an important role in cellular metabolism and is associated with tumorigenesis, suggesting an involvement in cell cycle progression. However, the underlying mechanisms mediating its involvement in these processes remain unclear. To elucidate the signaling pathways involved in PGC-1α function, we established a cell line, CH1 PGC-1α, which stably overexpresses PGC-1α. Using this cell line, we found that over-expression of PGC-1α stimulated extra adenosine triphosphate (ATP) and reduced reactive oxygen species (ROS) production. These effects were accompanied by up-regulation of the cell cycle checkpoint regulators CyclinD1 and CyclinB1. We hypothesized that ATP and ROS function as cellular signals to regulate cyclins and control cell cycle progression. Indeed, we found that reduction of ATP levels down-regulated CyclinD1 but not CyclinB1, whereas elevation of ROS levels down-regulated CyclinB1 but not CyclinD1. Furthermore, both low ATP levels and elevated ROS levels inhibited cell growth, but PGC-1α was maintained at a constant level. Together, these results demonstrate that PGC-1α regulates cell cycle progression through modulation of CyclinD1 and CyclinB1 by ATP and ROS. These findings suggest that PGC-1α potentially coordinates energy metabolism together with the cell cycle.
过氧化物酶体增殖物激活受体γ共激活因子1α（PGC-1α）是一种转录共激活因子，参与线粒体生物合成、呼吸能力和氧化磷酸化（OXPHOS）。PGC-1α在细胞代谢中起重要作用，并与肿瘤发生相关，提示其参与细胞周期进程。然而，介导其参与这些过程的潜在机制仍不清楚。为了阐明参与PGC-1α功能的信号通路，我们建立了一种稳定过表达PGC-1α的细胞系CH1 PGC-1α。利用该细胞系，我们发现PGC-1α的过表达刺激了额外三磷酸腺苷（ATP）的产生并减少了活性氧（ROS）的生成。这些效应伴随着细胞周期检查点调节因子细胞周期蛋白D1（CyclinD1）和细胞周期蛋白B1（CyclinB1）的上调。我们推测ATP和ROS作为细胞信号来调节细胞周期蛋白并控制细胞周期进程。事实上，我们发现ATP水平的降低下调了CyclinD1但未下调CyclinB1，而ROS水平的升高下调了CyclinB1但未下调CyclinD1。此外，低ATP水平和升高的ROS水平均抑制细胞生长，但PGC-1α保持在恒定水平。总之，这些结果表明PGC-1α通过ATP和ROS对CyclinD1和CyclinB1的调节来调控细胞周期进程。这些发现提示PGC-1α可能将能量代谢与细胞周期协调起来。
