Disruption of G1-phase phospholipid turnover by inhibition of Ca2+-independent phospholipase A2 induces a p53-dependent cell-cycle arrest in G1 phase.
J Cell Sci
; 119(Pt 6): 1005-15, 2006 Mar 15.
Article
em En
| MEDLINE
| ID: mdl-16492706
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 CTPphosphocholine 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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Fosfolipases A
/
Fase G1
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Proteína Supressora de Tumor p53
Idioma:
En
Ano de publicação:
2006
Tipo de documento:
Article