Involvement of the Interaction between p21 and Proliferating Cell Nuclear Antigen for the Maintenance of G2/M Arrest after DNA Damage

Abstract

Although a major effect of p21, a cyclin-dependent kinase inhibitor, is considered to be exerted during G 1 phase of the cell cycle, p21 gene knock-out studies suggested its involvement in G 2 /M checkpoint as well. Here we demonstrate evidence that p21 is required for the cell cycle arrest at G 2 upon DNA damage. We found that expression of wild-type p21 (p21 WT ), not mutant p21 (p21 PCNA؊ ) lacking the interaction with proliferating cell nuclear antigen (PCNA), caused G 2 cell cycle arrest in p53-deficient DLD1 colon cancer cell line after the DNA damage by treatment with cis-diamminedichloroplatinum (II). We also found that p21 WT was associated with Cdc2/cyclin B1 together with PCNA. Furthermore, coimmunoprecipitation experiments revealed that PCNA interacted with Cdc25C at the G 2 /M transition, and this interaction was abolished when p21WT was expressed presumably due to the competition between p21 WT and Cdc25C in the binding to PCNA. These findings suggest that p21 plays a regulatory role in the maintenance of cell cycle arrest at G 2 by blocking the interaction of Cdc25C with PCNA.

hSSB1 regulates both the stability and the transcriptional activity of p53

“…p21 is one of the critical target genes that mediates p53-induced cell cycle arrest. Much evidence has been presented showing that both p53 and p21 participate in arrest at the G1/S and G2/M checkpoints after DNA damage [47][48][49][50]. Our results show that hSSB1 is required to stabilize both p53 and p21 in response to IR ( Figure 5A) [28], and that hSSB1 knockdown allows bypass of the G2/M checkpoint response to IR.…”

H2O2 Induces a Transient Multi-phase Cell Cycle Arrest in Mouse Fibroblasts through Modulating Cyclin D and p21Cip1 Expression

“…Cip1 and PCNA co-operate to maintain cell cycle arrest at G 2 after DNA damage (56). Moreover, another study also demonstrated that p21…”

siRNA-mediated Silencing of Notch-1 Enhances Docetaxel Induced Mitotic Arrest and Apoptosis in PCa Cells

“…p21 waf1/cip1 is also known to promote G 2 /M arrest because the introduction of nonfunctional p21 waf1/cip1 or a p21 waf1/cip1 antisense oligonucleotide diminished the G 2 /M arrest phenotype in various cancer cell lines (Rigberg et al, 1999;De Siervi et al, 2004). It has been proposed that the interaction of p21 waf1/cip1 with proliferating cell nuclear antigen is critical for inducing G 2 cell cycle arrest (Ando et al, 2001). Therefore, G 2 /M cell cycle arrest induced by Notch-1 knockdown in prostate cancer cells is also attributed to the induction of p21 waf1/cip1 .…”