S-phase lengthening induced by p16INK4a overexpression in malignant cells with wild-type pRb and p53 - ENS de Lyon - École normale supérieure de Lyon Accéder directement au contenu
Article Dans Une Revue Cell Cycle Année : 2010

S-phase lengthening induced by p16INK4a overexpression in malignant cells with wild-type pRb and p53

Résumé

The p16INK4a protein is considered to regulate the cell cycle progression mainly by inhibiting cyclin-dependent kinases (CDKs) 4 and 6 activity and leading to an arrest in G0/G1. Here, we report that ectopic expression of p16INK4a in three p16-/ pRbWt/p53Wt human cancer cell lines MCF7, U2OS and U87 induces S-phase lengthening along with G1 accumulation. S-phase lengthening is suggested by the discrepancy between the unchanged or even increased percentage of cells in S phase found by flow cytometry DNA content analysis and the drop of BrdU labelling, and demonstrated by IdU/BrdU double labelling. p16INK4a induces a profound decrease in the CDK4/6-mediated pRb phosphorylation on Ser-807/811, a downregulation of CDK2 and CDK1 protein expression independently of G1 accumulation, and a decrease in Thr/Pro phosphorylation in part carried out by CDKs. In MCF7 cells, overexpression of the p16 G101W mutant, which is unable to inhibit CDK4/6 kinase activity and shows a modified subcellular localization, does not provoke the S-phase lengthening and the inhibition of Ser807/811-pRB and of Thr/Pro phosphorylation as wild-type p16INK4a does. Our results demonstrate that p16INK4a induces a S-phase lengthening independently of cellular origin. The CDK4/6 kinase activity inhibition together with the reduced expression of CDK2 and CDK1 acting downstream of G1 phase may prevent cells from any possible kinasic compensatory mechanisms, and thus lead to a cell cycle progression inhibition.
Fichier non déposé

Dates et versions

ensl-00815593 , version 1 (19-04-2013)

Identifiants

  • HAL Id : ensl-00815593 , version 1

Citer

Wei Wen Chien, Carine Domenech, Régine Catallo, Gilles Salles, Martine Ffrench. S-phase lengthening induced by p16INK4a overexpression in malignant cells with wild-type pRb and p53. Cell Cycle, 2010, 9 (16), pp.3306 - 3316. ⟨ensl-00815593⟩
44 Consultations
0 Téléchargements

Partager

Gmail Facebook X LinkedIn More