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c-Abl phosphorylates Hdm2 at tyrosine 276 in response to DNA damage and regulates interaction with ARF

Oncogene volume 25, pages 6666–6671 (2006)Cite this article

Abstract

The p53 tumour-suppressor protein is tightly regulated through its association with the Hdm2 E3 ligase. Activation of p53 by DNA strand breaks is orchestrated by the ataxia-telangiectasia mutated (ATM) protein kinase and involves interruption of Hdm2-mediated p53 degradation. As part of this mechanism ATM itself, and the ATM-activated protein tyrosine kinase, c-Abl, inhibit Hdm2 function through phosphorylation of serine 395 and tyrosine 394 (Y394), respectively. In the present study, we have identified a novel target of c-Abl in the Hdm2 protein, tyrosine 276 (Y276). We show that c-Abl phosphorylates this residue in vitro and confirm that Y394 is a target of c-Abl. We also show that Y276 is phosphorylated in a c-Abl-dependent manner in cultured cells and provide evidence that Y276 is phosphorylated in response to DNA damage coincident with the activation of c-Abl. Finally, we show that Y276 phosphorylation stimulates interaction with ARF, leading to increased levels of nucleolar Hdm2 and decreased turnover of p53. These data establish Y276 as a physiological target of c-Abl that contributes functionally to the induction of p53.

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Acknowledgements

We are extremely grateful to Giulio Superti-Furga for the gift of plasmids expressing the c-Abl kinase, to Sonia Lain for ARF-expressing plasmid and antibody to Mark Saville for purified Hdm2 and to Frances Fuller-Pace for assistance with immunofluorescence microscopy. This work was supported by the Biomedical Research Centre (University of Dundee), the Association for International Cancer Research and Cancer Research UK.

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  1. Molecular Signalling Group, Biomedical Research Centre, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK

    S S Dias, D M Milne & D W Meek

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  1. S S Dias
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  2. D M Milne
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  3. D W Meek
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Correspondence to D W Meek.

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Dias, S., Milne, D. & Meek, D. c-Abl phosphorylates Hdm2 at tyrosine 276 in response to DNA damage and regulates interaction with ARF. Oncogene 25, 6666–6671 (2006). https://doi.org/10.1038/sj.onc.1209671

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