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ATM activity contributes to the tumor-suppressing functions of p14ARF

Oncogene volume 23, pages 7355–7365 (2004)Cite this article

Abstract

P14/p19ARF (ARF) plays a major role in the activation of p53 by oncogenic signals. The biochemical basis of this has not been fully elucidated. We report here that forced expression of p14ARF enhances phosphorylation of p53 serine 15 (p53S15) in NIH3T3, IMR90 and MCF7 cells. Ectopic expression of the oncogenes c-myc, E2F1 and E1A, all of which activate p53 at least partially via ARF, lead to p53S15 phosphorylation in IMR90 cells. In addition, ectopic expression of p53 also results in p53S15 phosphorylation, suggesting that this is a common event in the ARF–p53 tumor suppression system. Furthermore, p53-, p14ARF-, c-myc- and E2F1-, but not E1A-, induced p53S15 phosphorylation was substantially reduced in AT fibroblasts (GM05823). Downregulation of ATM in MCF7 cells using RNA interference (RNAi) technology significantly attenuated p14ARF- and p53-induced phosphorylation of p53S15. Ectopically expressed ARF in NIH3T3 cells induced ATM nuclear foci and activated ATM kinase. Functionally, ectopic expression of p14ARF and c-myc inhibited the proliferation of IMR90 but not ATM null GM05823 cells, and p14ARF-induced inhibition of MCF7 cell proliferation was significantly attenuated by downregulation of ATM by RNAi. Taken together, these data show a functional role for ATM in ARF-mediated tumor suppression.

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Acknowledgements

We thank Drs Joseph R Nevins of Duke University and Frank Graham of McMaster University for providing E2F1 and E1A, respectively. This work was supported in part by the National Cancer Institute of Canada (grant no. 13009 200), a grant of Kidney Foundation of Canada, Canadian Foundation for Innovation (grant no. 6987) all to DT and a grant from the Canadian Institutes of Heath Research to AI. We like to dedicate this work to Dr Vincent J Kidd, member (professor) of St Jude Children's Research Hospital, who suddenly passed away on May 7, 2004.

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  1. Yanxia Li and Dongcheng Wu: These authors contributed equally to this work

Authors and Affiliations

  1. Division of Nephrology, Department of Medicine, McMaster University, Hamilton, ON, Canada

    Yanxia Li, Biao Chen, Alistair Ingram, Lizhi He & Damu Tang

  2. Father Sean O’Sullivan Research Institute, St Joseph's Hospital, Hamilton, ON, Canada

    Dongcheng Wu, Alistair Ingram, Lieqi Liu, Anil Kapoor & Damu Tang

  3. Department of Biochemistry, National Laboratory of Medical Molecular Biology, Peking Union Medical College, Beijing, People's Republic of China

    Dahai Zhu

  4. Department of Surgery, McMaster University, Canada

    Anil Kapoor

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  1. Yanxia Li
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Correspondence to Damu Tang.

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Li, Y., Wu, D., Chen, B. et al. ATM activity contributes to the tumor-suppressing functions of p14ARF. Oncogene 23, 7355–7365 (2004). https://doi.org/10.1038/sj.onc.1207957

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