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

Xu Hannah Zhang, Chunying Zhao, Konstantin Seleznev, Keying Song, James J. Manfredi, Zhongmin Alex Ma

Research output: Contribution to journalArticlepeer-review

51 Scopus citations

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 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 p2lcip1. 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 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.

Original languageEnglish
Pages (from-to)1005-1015
Number of pages11
JournalJournal of Cell Science
Volume119
Issue number6
DOIs
StatePublished - 15 Mar 2006

Keywords

  • Ca-independent Phospholiphase A
  • P53-dependent G1 arrest
  • Phospholipid turnover

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