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p14ARF induces G2 arrest and apoptosis independently of p53 leading to regression of tumours established in nude mice

Oncogene volume 22, pages 1822–1835 (2003)Cite this article

A Correction to this article was published on 19 April 2021

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Abstract

Until recently, the ability of ARF (human p14ARF, murine p19ARF) tumour-suppressor protein, encoded by the INK4A/ARF locus, to inhibit cell growth in response to various stimuli was related to its ability to stabilize p53 through the so-called ARF/MDM2/p53 pathway. However, recent data have demonstrated that ARF is not implicated in this unique p53-dependent pathway. By use of transient and stable expression, we show here that human p14ARF inhibits the growth of human tumoral cells lacking functional p53 by inducing a transient G2 arrest and subsequently apoptosis. This p14ARF–induced G2 arrest was correlated with inhibition of CDC2 activity, inactivation of CDC25C phosphatase and induction of the CDK inhibitor p21WAFI. Apoptosis was demonstrated using Hoechst 33352 staining, proteolytic activation of caspase-3 and PARP cleavage. Similar results were obtained in experiments with cells synchronized by hydroxyurea block. Importantly, we were able to reproduce these effects ‘in vivo’ by showing that p14ARF inhibits the growth of p53 nullizygous human tumours in nude mice and induces the regression of p53 −/− established tumours. In these experiments, tumoral regression was associated with inhibition of cell proliferation as well as induction of apoptosis confirming the data obtained in cell lines.

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Acknowledgements

This work was supported by a grant to EB from La Ligue Nationale Contre le Cancer as an ‘équipe Pabefliseeacute;’ and by the Association pour la Recherche le Cancer. BE was supported by INSERM; (Poste Accueil). We thank Christine Oddou, Pascal Perron, Christine Claraz and Sylvie Veyrenc for technical assistance.

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  1. Groupe de Recherche sur le Cancer du Poumon, EA 2021, Equipe INSERM 9924, Institut Albert Bonniot, La Tronche, 38706, Cedex, France

    Béatrice Eymin, Camille Leduc, Jean-Luc Coll, Elisabeth Brambilla & Sylvie Gazzeri

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  1. Béatrice Eymin
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  2. Camille Leduc
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Correspondence to Sylvie Gazzeri.

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Eymin, B., Leduc, C., Coll, JL. et al. p14ARF induces G2 arrest and apoptosis independently of p53 leading to regression of tumours established in nude mice. Oncogene 22, 1822–1835 (2003). https://doi.org/10.1038/sj.onc.1206303

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