NS1- and Minute Virus of Mice-Induced Cell Cycle Arrest: Involvement of p53 and p21 cip1

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Abstract
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 G 1 , S, and G 2 , well reproducing the arrest in S and G 2 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 p21 cip1 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 p21 cip1 . By comparison, MVMp infection induced the accumulation of both p53 and p21 cip1 . We demonstrate that p53 plays an essential role in the MVMp-induced cell cycle arrest in both S and G 2 by using p53 wild-type (+/+) and null (−/−) cells. Furthermore, only the G 2 arrest was abrogated in p21 cip1 null (−/−) cells. Together these results show that the MVMp-induced cell cycle arrest in S is p53 dependent but p21 cip1 independent, whereas the arrest in G 2 depends on both p53 and its downstream effector p21 cip1 . They also suggest that induction of p21 cip1 by the viral protein NS1 arrests cells in G 2 through inhibition of cyclin A-dependent kinase activity.