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Arf tumor suppressor disrupts the oncogenic positive feedback loop including c-Myc and DDX5

Oncogene volume 34, pages 314–322 (2015)Cite this article

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Abstract

Tumor suppressor protein p19ARF (Arf; p14ARF in humans) functions in both p53-dependent and -independent modes to counteract hyper-proliferative signals caused by proto-oncogene activation, but its p53-independent activities remain poorly understood. Using the tandem affinity purification-tag technique, we purified Arf-containing protein complexes and identified p68 DEAD-box protein (DDX5) as a novel interacting protein of Arf. In this study, we found that DDX5 interacts with c-Myc, and harbors essential roles for c-Myc-mediated transcription and its transforming activity. Furthermore, when c-Myc was forcibly expressed, the expression level of DDX5 protein was drastically increased through the acceleration of protein synthesis of DDX5, suggesting the presence of an oncogenic positive feedback loop including c-Myc and DDX5. Strikingly, Arf blocked the physical interaction between DDX5 and c-Myc, and drove away DDX5 from the promoter of c-Myc target genes. These observations most likely indicate the mechanism by which Arf causes p53-independent tumor-suppressive activity.

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Acknowledgements

We thank Charles Sherr and Martine Roussel for critical advice and reagents, and Michael Washburn of Stowers Institute for Medical Research Proteomics Center for performing MudPIT analysis. This work was supported by a grant-in-aid for scientific research from the MEXT (20770103), MEXT-supported program for the strategic research foundation at private universities (2013–2017) and the Takeda Science Foundation.

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Authors and Affiliations

  1. Division of Structural Biochemistry, Department of Biochemistry, School of Medicine, Jichi Medical University, Shimotsuke-shi, Japan

    K Tago & K Yanagisawa

  2. Department of Biochemistry, Faculty of Pharmacy, Keio University, Minato-ku, Japan

    M Funakoshi-Tago

  3. Department of Cell Biology, Laboratory of Signal Transduction, Graduate School of Biological Sciences, Nara Institute of Science and Technology, Ikoma, Japan

    H Itoh

  4. Division of Stem Cell Regulation, Center for Molecular Medicine, Jichi Medical University, Shimotsuke-shi, Japan

    Y Furukawa & J Kikuchi

  5. Department of Surgery, Saitama Medical Center, Jichi Medical University, Omiya-ku, Japan

    T Kato & K Suzuki

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Correspondence to K Tago.

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Tago, K., Funakoshi-Tago, M., Itoh, H. et al. Arf tumor suppressor disrupts the oncogenic positive feedback loop including c-Myc and DDX5. Oncogene 34, 314–322 (2015). https://doi.org/10.1038/onc.2013.561

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