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First published online 21 February 2006
doi: 10.1242/jcs.02821

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

¹ Division of Experimental Diabetes and Aging, Department of Geriatrics and Adult Development, Mount Sinai School of Medicine, New York, NY 10029, USA
² Department of Oncological Sciences, Mount Sinai School of Medicine, New York, NY 10029, USA

^* Author for correspondence (e-mail: zhongmin.ma{at}mssm.edu)

Accepted 2 December 2005

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 VI 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 p21^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 activation of p53 and expression 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.

Key words: Ca²⁺-independent Phospholipase A₂, phospholipid turnover, p53-dependent G1 arrest

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