Disruption of G1-phase phospholipid turnover by inhibition of Ca2+-independent phospholipase A2 induces a p53-dependent cell-cycle arrest in G1 phase
Open Access
- 15 March 2006
- journal article
- Published by The Company of Biologists in Journal of Cell Science
- Vol. 119 (6), 1005-1015
- https://doi.org/10.1242/jcs.02821
Abstract
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.Keywords
This publication has 55 references indexed in Scilit:
- Male Mice That Do Not Express Group VIA Phospholipase A2 Produce Spermatozoa with Impaired Motility and Have Greatly Reduced FertilityJournal of Biological Chemistry, 2004
- The Ankrd2 Protein, a Link Between the Sarcomere and the Nucleus in Skeletal MuscleJournal of Molecular Biology, 2004
- The Crystal Structure of Gankyrin, an Oncoprotein Found in Complexes with Cyclin-dependent Kinase 4, a 19 S Proteasomal ATPase Regulator, and the Tumor Suppressors Rb and p53Published by Elsevier ,2004
- Bromoenol Lactone Promotes Cell Death by a Mechanism Involving Phosphatidate Phosphohydrolase-1 Rather than Calcium-independent Phospholipase A2Journal of Biological Chemistry, 2003
- The emerging role of lysophosphatidic acid in cancerNature Reviews Cancer, 2003
- Apoptotic Cells Induce Migration of Phagocytes via Caspase-3-Mediated Release of a Lipid Attraction SignalCell, 2003
- Live or let die: the cell's response to p53Nature Reviews Cancer, 2002
- Regulation of p53 stability by Mdm2Nature, 1997
- Mdm2 promotes the rapid degradation of p53Nature, 1997
- Structure of the p53 Tumor Suppressor Bound to the Ankyrin and SH3 Domains of 53BP2Science, 1996