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p14ARF activates a Tip60-dependent and p53-independent ATM/ATR/CHK pathway in response to genotoxic stress.

Abstract : 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.
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Contributor : Danielle Salas Connect in order to contact the contributor
Submitted on : Monday, October 1, 2007 - 2:29:52 PM
Last modification on : Friday, November 6, 2020 - 3:46:16 AM

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Béatrice Eymin, Paule Claverie, Caroline Salon, Camille Leduc, Edwige Col, et al.. p14ARF activates a Tip60-dependent and p53-independent ATM/ATR/CHK pathway in response to genotoxic stress.. Molecular and Cellular Biology, American Society for Microbiology, 2006, 26 (11), pp.4339-50. ⟨10.1128/MCB.02240-05⟩. ⟨inserm-00175818⟩



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