• Open Access

Translation-dependent mechanisms lead to PML upregulation and mediate oncogenic K-RAS-induced cellular senescence

Authors

  • Pier Paolo Scaglioni,

    Corresponding author
    1. Cancer Biology and Genetics Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
    2. Department of Medicine, Division of Hematology and Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA
    • Pier Paolo Scaglioni, Tel: +1 214 645 6449; Fax: +1 214 645 5915

      Pier Paolo Pandolfi, Tel: +1 617 667 3289; Fax: +1 617 667 0610

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  • Andrea Rabellino,

    1. Department of Medicine, Division of Hematology and Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA
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    • These authors contributed equally to this work

  • Thomas M. Yung,

    1. Cancer Biology and Genetics Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
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    • These authors contributed equally to this work

  • Rosa Bernardi,

    1. Cancer Biology and Genetics Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
    2. Cancer Genetics Program, Beth Israel Deaconess Cancer Center. Division of Genetics, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
    3. Present address: Division of Molecular Oncology, San Raffaele Scientific Institute, Milano, Italy
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  • Sooyeon Choi,

    1. Department of Medicine, Division of Hematology and Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA
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  • Georgia Konstantinidou,

    1. Department of Medicine, Division of Hematology and Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA
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  • Caterina Nardella,

    1. Cancer Biology and Genetics Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
    2. Cancer Genetics Program, Beth Israel Deaconess Cancer Center. Division of Genetics, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
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  • Ke Cheng,

    1. Cancer Biology and Genetics Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
    2. Cancer Genetics Program, Beth Israel Deaconess Cancer Center. Division of Genetics, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
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  • Pier Paolo Pandolfi

    Corresponding author
    1. Cancer Biology and Genetics Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
    2. Cancer Genetics Program, Beth Israel Deaconess Cancer Center. Division of Genetics, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
    • Pier Paolo Scaglioni, Tel: +1 214 645 6449; Fax: +1 214 645 5915

      Pier Paolo Pandolfi, Tel: +1 617 667 3289; Fax: +1 617 667 0610

    Search for more papers by this author

Abstract

Expression of oncogenic K-RAS in primary cells elicits oncogene-induced cellular senescence (OIS), a form of growth arrest that potently opposes tumourigenesis. This effect has been largely attributed to transcriptional mechanisms that depend on the p53 tumour suppressor protein. The PML tumour suppressor was initially identified as a component of the PML-RARα oncoprotein of acute promyelocytic leukaemia (APL). PML, a critical OIS mediator, is upregulated by oncogenic K-RAS in vivo and in vitro. We demonstrate here that oncogenic K-RAS induces PML protein upregulation by activating the RAS/MEK1/mTOR/eIF4E pathway even in the absence of p53. Under these circumstances, PML mRNA is selectively associated to polysomes. Importantly, we find that the PML 5′ untranslated mRNA region plays a key role in mediating PML protein upregulation and that its presence is essential for an efficient OIS response. These findings demonstrate that upregulation of PML translation plays a central role in oncogenic K-RAS-induced OIS. Thus, selective translation initiation plays a critical role in tumour suppression with important therapeutic implications for the treatment of solid tumours and APL.

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