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The tumor suppressor, TAX1BP2, is a novel substrate of ATM kinase

Oncogene volume 33, pages 5303–5309 (2014)Cite this article

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Abstract

DNA damage repair response is a crucial process for cancer prevention. One of the key regulators of this process is ataxia telangiectasia mutated (ATM) kinase, which modulates the p53 level by direct and indirect phosphorylation. Recent data showed that ATM also localizes at the centrosome, but the function remains elusive. TAX1BP2 was initially identified as a novel centrosomal protein that interacts directly with the human T-cell leukemia virus type 1 (HTLV-1)-encoded oncoprotein, Tax, and inhibits centrosome overduplication. Subsequently, TAX1BP2 was found to be a tumor suppressor in hepatocellular carcinoma, and accumulation of TAX1BP2 was observed upon chemotherapeutic drug treatment. Here, we provide evidence that TAX1BP2 is a direct phosphorylation substrate of ATM. The protein level of TAX1BP2 is significantly upregulated in response to DNA damaging agents. Serine-922 of TAX1BP2 is the phosphorylation site of ATM, and such phosphorylation modulates the protein stability, ubiquitination and tumor suppressor activity of TAX1BP2. Taken together, we demonstrate for the first time that TAX1BP2 is a novel effector of ATM in DNA damage response and delineated a new mechanism by which ATM stabilizes the tumor suppressor TAX1BP2.

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Acknowledgements

We are very grateful to Prof Jin DY for providing the HA-p38-expressing plasmid, Prof SW Tsao for providing the anti-Chk1 and anti-Chk2 antibodies and Dr MS Huen for providing the FLAG-ubiquitin-expressing plasmid. Financial support was received from the Hong Kong Health and Medical Research Fund (No. 12110872), the Hong Kong Research Grant Council (HKU 763509 and 7/CRF/09), the SK Yee Medical Research Fund 2011 (to YPC) and The University of Hong Kong (Small Project Funding 201209176008 to WLL).

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Authors and Affiliations

  1. Department of Anatomy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China

    W L Lai, W Y Hung & Y P Ching

  2. State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, China

    Y P Ching

  3. State Key Laboratory of Brain and Cognitive Sciences, The University of Hong Kong, Hong Kong, China

    Y P Ching

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  1. W L Lai
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  2. W Y Hung
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  3. Y P Ching
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Correspondence to Y P Ching.

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Lai, W., Hung, W. & Ching, Y. The tumor suppressor, TAX1BP2, is a novel substrate of ATM kinase. Oncogene 33, 5303–5309 (2014). https://doi.org/10.1038/onc.2013.481

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