• Open Access

Pml represses tumour progression through inhibition of mTOR

Authors

  • Rosa Bernardi,

    Corresponding author
    1. 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
    2. Current address: Division of Molecular Oncology, San Raffaele Scientific Institute, Via Olgettina 60, Milano 20132, Italy
    • Tel: +39 02 2643 5606; Fax: +39 02 2643 5602
    Search for more papers by this author
  • Antonella Papa,

    1. 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
    Search for more papers by this author
  • Ainara Egia,

    1. 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
    Search for more papers by this author
  • Nadia Coltella,

    1. 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
    2. Division of Molecular Oncology, San Raffaele Scientific Institute, Milano, Italy
    Search for more papers by this author
  • Julie Teruya-Feldstein,

    1. Department of Pathology, Memorial Sloan-Kettering Cancer Center, Sloan-Kettering Institute, New York, NY, USA
    Search for more papers by this author
  • Sabina Signoretti,

    1. Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
    Search for more papers by this author
  • Pier Paolo Pandolfi

    Corresponding author
    1. 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
    • Tel: +1 617 735 2145; Fax: +1 617 735 2120
    Search for more papers by this author

Abstract

The promyelocytic leukaemia gene PML is a pleiotropic tumour suppressor. We have recently demonstrated that PML opposes mTOR-HIF1α-VEGF signalling in hypoxia. To determine the relevance of PML-mTOR antagonism in tumourigenesis, we have intercrossed Pml null mice with Tsc2 heterozygous mice, which develop kidney cysts and carcinomas exhibiting mTOR upregulation. We find that combined inactivation of Pml and Tsc2 results in aberrant TORC1 activity both in pre-tumoural kidneys as well as in kidney lesions. Such increase correlates with a marked acceleration in tumour progression, impacting on both the biology and histology of kidney carcinomas. Also, Pml inactivation decreases the rate of loss of heterozygosity (LOH) for the wt Tsc2 allele. Interestingly, however, aberrant TORC1 activity does not accelerate renal cystogenesis in Tsc2/Pml mutants. Our data demonstrate that activation of mTOR is critical for tumour progression, but not for tumour initiation in the kidney.

Ancillary