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Molecular and Cellular Biology, June 2006, p. 4339-4350, Vol. 26, No. 11
0270-7306/06/$08.00+0     doi:10.1128/MCB.02240-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

p14ARF Activates a Tip60-Dependent and p53-Independent ATM/ATR/CHK Pathway in Response to Genotoxic Stress

Béatrice Eymin,1,{dagger} Paule Claverie,1,{dagger} Caroline Salon,1 Camille Leduc,1 Edwige Col,2 Elisabeth Brambilla,1 Saadi Khochbin,2 and Sylvie Gazzeri1*

INSERM U578, Institut Albert Bonniot, Université Joseph Fourier, Faculté de Medecine, Groupe de Recherche sur le Cancer du Poumon, 38706 La Tronche Cedex, France,1 INSERM U309, Institut Albert Bonniot, Université Joseph Fourier, Laboratoire de Biologie Moléculaire et Cellulaire de la Différenciation, 38706 La Tronche Cedex, France2

Received 21 November 2005/ Returned for modification 13 December 2005/ Accepted 7 March 2006

p14ARF is a tumor suppressor that controls a well-described p53/Mdm2-dependent checkpoint in response to oncogenic signals. Here, new insights into the tumor-suppressive function of p14ARF are provided. We previously showed that p14ARF can induce a p53-independent G2 cell cycle arrest. In this study, we demonstrate that the activation of ATM/ATR/CHK signaling pathways contributes to this G2 checkpoint and highlight the interrelated roles of p14ARF and the Tip60 protein in the initiation of this DNA damage-signaling cascade. We show that Tip60 is a new direct p14ARF binding partner and that its expression is upregulated and required for ATM/CHK2 activation in response to p14ARF. Strikingly, both p14ARF and Tip60 products accumulate following a cell treatment with alkylating agents and are absolutely required for ATM/CHK2 activation in this setting. Moreover, and consistent with p14ARF being a determinant of CHK2 phosphorylation in lung carcinogenesis, a strong correlation between p14ARF and phospho-CHK2 (Thr68) protein expression is observed in human lung tumors (P < 0.00006). Overall, these data point to a novel regulatory pathway that mediates the p53-independent negative-cell-growth control of p14ARF. Inactivation of this pathway is likely to contribute to lung carcinogenesis.

* Corresponding author. Mailing address: Groupe de Recherche sur le Cancer du Poumon, INSERM U578, Institut Albert Bonniot, 38706 La Tronche Cedex, France. Phone: 33 4 76 54 95 53. Fax: 33 4 76 54 94 13. E-mail: Sylvie.Gazzeri{at}ujf-grenoble.fr.

{dagger} Both authors contributed equally to this work.

Molecular and Cellular Biology, June 2006, p. 4339-4350, Vol. 26, No. 11
0270-7306/06/$08.00+0     doi:10.1128/MCB.02240-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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