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Journal of Virology, November 2001, p. 11071-11078, Vol. 75, No. 22
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.22.11071-11078.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

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

Anne Op De Beeck,^1,2,* Joelle Sobczak-Thepot,^3, Huseyin Sirma,^3, Florence Bourgain,^3, Christian Brechot,³ and Perrine Caillet-Fauquet^2,4,§

Laboratoire de Biophysique et Radiobiologie² and Laboratoire de Virologie Moléculaire CP614, Faculté de médecine,⁴ Université Libre de Bruxelles, 1070 Brussels, Belgium; Laboratoire de Carcinogenèse Hépatique et Virologie Moléculaire, Unité INSERM 370, Faculté Necker, Paris, France³; and Unité Hépatite C, CNRS-FRE 2369, Institut de Biologie de Lille et Institut Pasteur de Lille, 59021 Lille cedex, France¹

Received 7 May 2001/Accepted 12 June 2001

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 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 G₂ by using p53 wild-type (+/+) and null (/) cells. Furthermore, only the G₂ 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 G₂ 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 G₂ through inhibition of cyclin A-dependent kinase activity.

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^* Corresponding author. Present address: Unité Hépatite C, CNRS-FRE 2369, Institut de Biologie de Lille et Institut Pasteur de Lille, 1, rue du Prof. Calmette, BP447, 59021 Lille Cedex, France. Phone: (33) 3 20 87 11 62. Fax: (33) 3 20 87 11 11. E-mail: anne.op-de-beeck{at}ibl.fr.

Present address: Biochimie Cellulaire, CNRS UMR 7088, Université P. & M. Curie, 75252 Paris Cedex 05, France.

Present address: Heinrich Pette Institut, Hamburg, Germany.

^§ Present address: Laboratoire de Virologie Moléculaire CP614, Faculté de Médecine, Université Libre de Bruxelles, 1070 Brussels, Belgium.

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Journal of Virology, November 2001, p. 11071-11078, Vol. 75, No. 22
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.22.11071-11078.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

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