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 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 p21cip1. 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-p21cip1 checkpoint mechanism, thereby blocking the entry of G1-phase cells into S phase.
Division of Experimental Diabetes and Aging, Department of Geriatrics and Adult Development, Mount Sinai School of Medicine, New York, NY 10029, USA.
Xu Hannah
XH
Zhang
Chunying
C
Zhao
Konstantin
K
Seleznev
Keying
K
Song
James J
JJ
Manfredi
Zhongmin Alex
ZA
Ma
D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D016923:Cell Death / Q000502:physiology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis; D016193:G1 Phase / Q000187:drug effects / Q000502:physiology*; D005786:Gene Expression Regulation; D054522:Group VI Phospholipases A2; D006801:Humans; D009281:Naphthalenes / Q000494:pharmacology; D015739:Nocodazole / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010741:Phospholipases A / Q000037:antagonists & inhibitors / Q000502:physiology*; D054467:Phospholipases A2; D010743:Phospholipids / Q000378:metabolism; D011753:Pyrones / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D050759:Cyclin-Dependent Kinase Inhibitor p21; D009281:Naphthalenes; D010726:Phosphodiesterase Inhibitors; D010743:Phospholipids; D011753:Pyrones; D016159:Tumor Suppressor Protein p53; C068314:6-(bromomethylene)tetrahydro-3-(1-naphthaleneyl)-2H-pyran-2-one; D010741:Phospholipases A; D054522:Group VI Phospholipases A2; C516475:PLA2G6 protein, human; D054467:Phospholipases A2; D015739:Nocodazole