Disruption of G1-phase phospholipid turnover by inhibition of Ca²⁺-independent phospholipase A₂ induces a p53-dependent cell-cycle arrest in G1 phase

The G1 phase of the cell cycle is characterized by a high rate of membrane phospholipid turnover. Cells regulate this turnover by coordinating the opposing actions of CTP: phosphocholine cytidylyltransferase and the group V1 Ca²⁺-independent phospholipase A₂ (iPLA₂). However, little is known about how such turnover affects cell-cycle progression. Here, we show that G1-phase phospholipid turnover is essential for cell proliferation. Specific inhibition of iPLA² arrested cells in the G1 phase of the cell cycle. This G1-phase arrest was associated with marked upregulation of the tumour suppressor p53 and the expression of cyclin-dependent kinase inhibitor p2l^cip1. Inactivation of iPLA₂ failed to arrest p53-deficient HCT cells in the G1 phase and caused massive apoptosis of p21-deficient HCT cells, suggesting that this G1-phase arrest requires activition of p53 and expresion of p21^cip1. Furthermore, downregulation of p53 by siRNA in p21-deficient HCT cells reduced the cell death, indicating that inhibition of iPLA₂ induced p53-dependent apoptosis in the absence of p21^cip1. Thus, our study reveals hitherto unrecognized cooperation between p53 and iPLA₂ to monitor membrane-phospholipid turnover in G1 phase. Disrupting the G1-phase phospholipid turnover by inhibition of iPLA₂ activates the p53-p21^cip1 checkpoint mechanism, thereby blocking the entry of G1-phase cells into S phase.