Roles of pH in control of cell proliferation.

Precise spatiotemporal regulation of intracellular pH (pHi ) is a prerequisite for normal cell function, and changes in pHi or pericellular pH (pHe ) exert important signalling functions. It is well established that proliferation of mammalian cells is dependent on a permissive pHi 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 pHi ), which is secondary to activation of Na+ /H+ exchange. However, it remains controversial whether this increase in pHi 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 pHi in mammalian cell proliferation have focused on the mitogen-induced G0-G1 transition, and the regulation and roles of pHi during the cell cycle remain poorly understood. The aim of this review is to summarize and critically discuss the possible roles of pHi and pHe 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 pHi and discuss possible pHi - and pHe sensors and signalling pathways relevant to mammalian proliferation control. The possibility that changes in pHi 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.