Coordination of membrane phospholipid synthesis with the cell cycle

Abstract

The formation of membrane phospholipid is coordinated with the cell cycle in a colony-stimulating factor 1-dependent macrophage cell line. Net phospholipid accumulation occurs as cells enter S phase and results from an interaction between cell cycle-dependent oscillations in the rates of phosphatidylcholine (PtdCho) biosynthesis and degradation. CTP:phosphocholine cytidylyltransferase (CT) is the rate-controlling step in PtdCho biosynthesis, and its activity is inhibited by cell cycle-dependent phosphorylation. CT phosphorylation is low in early G1, begins to rise in late G1, increases steadily through S and G2/M, and then declines precipitously as cells exit mitosis and reenter G1. CT activity increases in early G1 and then decreases steadily as the cells progress through late G1, S, and G2/M, reflecting the elevated phosphorylation state of the protein. Membrane phospholipid degradation is also periodic: the rate is rapid in G1, slows significantly during S phase, and accelerates again as cells reenter G1. The data support the hypothesis that CT dephosphorylation accelerates PtdCho synthesis in response to the increased membrane phospholipid degradation to maintain membrane phospholipid mass during G1 and that the periodic cessation of phospholipid degradation during S phase accounts for the transition to net membrane phospholipid accumulation. Inactivation of CT associated with hyperphosphorylation of the protein during G2/M likely plays a determining role in the cessation of net membrane accumulation prior to cell division.