The membrane, magnesium, mitosis (MMM) model of cell proliferation control.

The proliferation of cells in culture requires the presence of growth factors in the medium, provided either by serum or purified proteins. Cells are made quiescent by contact inhibition and sharply diminishing the concentration of growth factors overnight; they are then stimulated by restoring the original high concentration of the growth factors. The addition activates a coordinated group of biochemical responses within minutes, that is followed in 5-12 hr by the onset of DNA synthesis and then mitosis. The most critical of the early responses for the later onset of DNA synthesis is an increase in the rate of protein synthesis, which must be maintained by the continued presence of the growth factors throughout the G1 period. Lowering the Mg2+ concentration of the medium and therefore within the cells, reduces all the early reactions of the coordinate response including protein synthesis, which is followed by a disproportionately large reduction in the rate of DNA synthesis. Stimulation in the presence of physiological concentration of Mg2+ raises the total Mg and the free Mg2+ of the cells for extended periods. Mg2+ in the form of MgATP2- is required for all the phosphorylation reactions of the cell. These and related observations are imaged in the membrane, magnesium, mitosis (MMM) model of cell proliferation control, which postulates that growth factors act by combining with membrane receptors to increase intracellular free Mg2+ levels and generate the coordinate response that leads ultimately to mitosis. The MMM model also proposes that the increased Mg2+ activates phosphorylation of two proteins by mTOR, a key reaction of the PI-3K pathway. Those two proteins directly regulate the initiation of protein synthesis, the driving force of the process.