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Identification of an ataxia telangiectasia-mutated protein mediated surveillance system to regulate Bcl-2 overexpression

Oncogene volume 25, pages 5601–5611 (2006)Cite this article

Abstract

Bcl-2 can both promote and attenuate tumorigenesis. Although the former function is relatively well characterized, the mechanism of the latter remains elusive. We report here that enforced Bcl-2 expression in MCF7 cells stabilizes p53, induces phosphorylation of p53 serine 15 (p53pSer15) and inhibits MCF7 cell growth. Consistent with p53 Ser15 being a target of ataxia telangiectasia mutated protein(ATM)/ATR (ATM- and rad3-related) in the DNA damage response, Bcl-2 activates ATM by inducing ATM Ser1981 phosphorylation, which is accompanied with the phosphorylaton of two additional ATM substrates, Chk2 Thr68 and H2AX Ser139. Downregulation of ATM using a specific small interference RNA fragment (ATMRNAi) abolished Bcl-2-induced p53pSer15 and Bcl-2-mediated growth inhibition of MCF7 cells. Ectopic expression of a dominant-negative p53 mutant, p53175H, partially rescued this growth inhibition. Taken together, these observations demonstrate the contribution of ATM-p53 function to Bcl-2-mediated inhibition of MCF7 cell growth, indicating an ATM-mediated surveillance system for regulating Bcl-2 overexpression. Consistent with this concept, we found that MCF7 cells express Bcl-2 heterogeneously with 34.5% of cells being Bcl-2 negative. In general, Bcl-2-positive MCF7 cells proliferate slower than those of Bcl-2 negative. Thus, we provide evidence suggesting that activation of ATM suppresses Bcl-2-induced tumorigenesis, and that attenuation of ATM function may be an important event in breast cancer progression.

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Acknowledgements

This work was supported by a CIHR Grant to D Tang. NIH Grant CA67938 to JMl/VJK and NIH Cancer Center Support Grant to St Jude Children's Research Hospital and support from ALSAC (American Syrian Lebanese Associated Charities) to JML/VJK. We are very grateful to Dr Tei Wei for his assistance.

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Author notes

  1. S Cormier

    Present address: Hill Park Secondary School, Hamilton, Ontario, Canada, L9A 4K6

Authors and Affiliations

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

    J Zhang, A Bruce, L He, K Parihar, C Fan, S Cormier & D Tang

  2. Department of Genetics and Tumor Cell Biology, St Jude Children's Research Hospital, Memphis, TN, USA

    J M Lahti, J Grenet & V J Kidd

  3. Father Sean O'Sullivan Research Institute, St Joseph's Hospital, McMaster University, Hamilton, Ontario, Canada

    L Liu & D Tang

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Correspondence to J M Lahti or D Tang.

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Zhang, J., Lahti, J., Bruce, A. et al. Identification of an ataxia telangiectasia-mutated protein mediated surveillance system to regulate Bcl-2 overexpression. Oncogene 25, 5601–5611 (2006). https://doi.org/10.1038/sj.onc.1209565

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