Mitogens and Ion Fluxes

Abstract

The response of growth-arrested cells to a variety of growth factors and pharmacological mitogens involves a cascade of biochemical and ionic changes that occur within minutes and are believed to play critical roles in the initiation of cell proliferation. In general, investigations of these phenomena have used proliferating cells in culture that can be made to reversibly enter the nonproliferative Go/Gt state, usually by the withdrawal of serum. The bio­ chemical changes observed within the first few minutes of the addition of growth factors and mitogens include protein phosphorylation, an increased turnover of inositol lipids, and increased transcription of several proto­ oncogenes. The ionic alterations include rapid increases in the cytosolic free calcium concentration ([Ca2+l) from intracellular calcium stores andlor ,via influx through channels in the plasma membrane and the stimulation of the plasma membrane Na+ -H+ exchanger, which promotes an increase in sodium influx and cytoplasmic alkalinization. The relationship between these early changes and the increase in DNA synthesis that occurs many hours later is a key question in the understanding of mitogenesis. This article focuses on the alterations in ion fluxes that have been observed in response to mitogens in a variety of cells. In addition, the association of biochemical events with ion fluxes and the association of these eady events with the subsequent initiation of DNA synthesis are discussed. Important considerations that arc addressed are whether there are multiple pathways by which different mitogens induce proliferation and whether a single mitogen can induce proliferation by multi­ ple pathways.