Journal
JOURNAL OF CELL SCIENCE
Volume 119, Issue 6, Pages 1005-1015Publisher
COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.02821
Keywords
Ca2+-independent Phospholipase A(2); phospholipid turnover; p53-dependent G1 arrest
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Funding
- NIDDK NIH HHS [R01 DK063076, R01 DK063076-03, R01 DK063076-02, R01 DK063076-01A1, R01DK063076] Funding Source: Medline
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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 A(2) (iPLA(2)). 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 p21cip1. 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 p21cip1. 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.
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