Phosphoinositide metabolism and control of cell proliferation

Abstract

In most cells initiation of DNA synthesis is inexorably followed by a premitotic phase and then by mitosis, the essential control of cell proliferation is therefore the signal that commits a cell to DNA synthesis. Since cells may be stimulated to divide from various degrees of preparedness these signals differ in their complexity. Nevertheless two general problems emerge that we must address in seeking to understand how mitogens stimulate cells to proliferate. Firstly, DNA synthesis occurs in the nucleus yet mitogens are recognised by their receptors in the plasma membrane: how do occupied receptors communicate, across the cytoplasm, with the nucleus? Secondly, while mitogens are immediately recognised by their receptors, DNA synthesis typically begins many hours later: what happens during this long interval? By the usual criteria of necessity and sufficiency, it is clear that the messengers that link early events at the plasma membrane with the later initiation of DNA synthesis have not been identified. Indeed it is very likely that there are many pathways from cell-surface receptors to the nucleus and these pathways overlap and interact so that no single intracellular messenger is likely to be both necessary and sufficient to commit a cell to DNA synthesis.