NS1- and Minute Virus of Mice-Induced Cell Cycle Arrest: Involvement of p53 and p21cip1

AUTOR(ES)

Op De Beeck, Anne

FONTE

American Society for Microbiology

RESUMO

The nonstructural protein NS1 of the autonomous parvovirus minute virus of mice (MVMp) is cytolytic when expressed in transformed cells. Before causing extensive cell lysis, NS1 induces a multistep cell cycle arrest in G1, S, and G2, well reproducing the arrest in S and G2 observed upon MVMp infection. In this work we investigated the molecular mechanisms of growth inhibition mediated by NS1 and MVMp. We show that NS1-mediated cell cycle arrest correlates with the accumulation of the cyclin-dependent kinase (Cdk) inhibitor p21cip1 associated with both the cyclin A/Cdk and cyclin E/Cdk2 complexes but in the absence of accumulation of p53, a potent transcriptional activator of p21cip1. By comparison, MVMp infection induced the accumulation of both p53 and p21cip1. We demonstrate that p53 plays an essential role in the MVMp-induced cell cycle arrest in both S and G2 by using p53 wild-type (+/+) and null (−/−) cells. Furthermore, only the G2 arrest was abrogated in p21cip1 null (−/−) cells. Together these results show that the MVMp-induced cell cycle arrest in S is p53 dependent but p21cip1 independent, whereas the arrest in G2 depends on both p53 and its downstream effector p21cip1. They also suggest that induction of p21cip1 by the viral protein NS1 arrests cells in G2 through inhibition of cyclin A-dependent kinase activity.

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