Section for Cell Biology and Physiology, Department of Biology, Faculty of Science, University of Copenhagen, Copenhagen, Denmark.
Acta Physiol (Oxf). 2018 Jul;223(3):e13068. doi: 10.1111/apha.13068. Epub 2018 Apr 16.
Precise spatiotemporal regulation of intracellular pH (pH ) is a prerequisite for normal cell function, and changes in pH or pericellular pH (pH ) exert important signalling functions. It is well established that proliferation of mammalian cells is dependent on a permissive pH in the slightly alkaline range (7.0-7.2). It is also clear that mitogen signalling in nominal absence of HCO3- is associated with an intracellular alkalinization (~0.3 pH unit above steady-state pH ), which is secondary to activation of Na /H exchange. However, it remains controversial whether this increase in pH is part of the mitogenic signal cascade leading to cell cycle entry and progression, and whether it is relevant under physiological conditions. Furthermore, essentially all studies of pH in mammalian cell proliferation have focused on the mitogen-induced G0-G1 transition, and the regulation and roles of pH during the cell cycle remain poorly understood. The aim of this review is to summarize and critically discuss the possible roles of pH and pH in cell cycle progression. While the focus is on the mammalian cell cycle, important insights from studies in lower eukaryotes are also discussed. We summarize current evidence of links between cell cycle progression and pH and discuss possible pH - and pH sensors and signalling pathways relevant to mammalian proliferation control. The possibility that changes in pH during cell cycle progression may be an integral part of the checkpoint control machinery is explored. Finally, we discuss the relevance of links between pH and proliferation in the context of the perturbed pH homoeostasis and acidic microenvironment of solid tumours.
精确的细胞内 pH 值（pH ）时空调节是正常细胞功能的前提，而 pH 值或细胞外 pH 值（pH ）的变化发挥着重要的信号作用。众所周知，哺乳动物细胞的增殖依赖于略微碱性范围（7.0-7.2）的许可 pH 值。同样清楚的是，在没有 HCO3- 的情况下，有丝分裂信号与细胞内碱化（比稳态 pH 值高约 0.3 pH 单位）有关，这是 Na+/H 交换激活的结果。然而，细胞内 pH 值的增加是否是导致细胞周期进入和进展的有丝分裂信号级联的一部分，以及它在生理条件下是否相关，仍然存在争议。此外，基本上所有关于哺乳动物细胞增殖中 pH 值的研究都集中在有丝分裂诱导的 G0-G1 过渡上，而 pH 值在细胞周期中的调节和作用仍然知之甚少。本文综述的目的是总结和批判性讨论 pH 值和 pH 值在细胞周期进展中的可能作用。虽然重点是哺乳动物细胞周期，但也讨论了低等真核生物研究的重要见解。我们总结了细胞周期进展与 pH 值之间联系的现有证据，并讨论了与哺乳动物增殖控制相关的可能的 pH 值和 pH 值传感器和信号通路。探讨了细胞周期进展过程中 pH 值变化是否可能是检查点控制机制的一个组成部分。最后，我们讨论了 pH 值与增殖之间的联系在肿瘤 pH 值稳态失调和酸性微环境中的相关性。
