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

Abstract : 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.
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Contributor : Agnès Ganivet <>
Submitted on : Friday, April 19, 2013 - 9:12:38 AM
Last modification on : Thursday, February 7, 2019 - 2:28:38 PM

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  • HAL Id : ensl-00815593, version 1
  • DOI : 10.4161

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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, Taylor & Francis, 2010, 9 (16), pp.3306 - 3316. ⟨10.4161⟩. ⟨ensl-00815593⟩

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