Antagonistic TSC22D1 variants control BRAFE600-induced senescence

Authors

  • Cornelia Hömig-Hölzel,

    1. Division of Molecular Genetics, The Netherlands Cancer Institute, Amsterdam, The Netherlands
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  • Remco van Doorn,

    1. Division of Molecular Genetics, The Netherlands Cancer Institute, Amsterdam, The Netherlands
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    • Present address: Department of Dermatology, Leiden University Medical Center, Leiden, The Netherlands
  • Celia Vogel,

    1. Division of Molecular Genetics, The Netherlands Cancer Institute, Amsterdam, The Netherlands
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  • Markus Germann,

    1. Department of Urology and Clinical Research, Urology Research Laboratory, University of Bern, Bern, Switzerland
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  • Marco G Cecchini,

    1. Department of Urology and Clinical Research, Urology Research Laboratory, University of Bern, Bern, Switzerland
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  • Els Verdegaal,

    1. Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands
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  • Daniel S Peeper

    Corresponding author
    1. Division of Molecular Genetics, The Netherlands Cancer Institute, Amsterdam, The Netherlands
    • Corresponding author. Division of Molecular Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, Room P1.011, Amsterdam 1066 CX, The Netherlands. Tel.: +31 20 5122 002; Fax: +31 20 5122 011; E-mail: d.peeper@nki.nl

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Abstract

Oncogene-induced cellular senescence (OIS) is an increasingly recognized tumour suppressor mechanism that confines the outgrowth of neoplastic cells in vivo. It relies on a complex signalling network, but only few components have been identified so far. Gene-expression profiling revealed a >100-fold increase in the levels of the transcription factor and putative tumour suppressor gene TGFβ-stimulated clone 22 (TSC22D1) in BRAFE600-induced senescence, in both human fibroblasts and melanocytes. Only the short TSC22D1 transcript was upregulated, whereas the abundance of the large protein variant was suppressed by proteasomal degradation. The TSC22D1 protein variants, in complex with their dimerization partner TSC22 homologue gene 1 (THG1), exerted opposing functions, as selective depletion of the short form, or conversely, overexpression of the large variant, resulted in abrogation of OIS. This was accompanied by the suppression of several inflammatory factors and p15INK4B, with TSC22D1 acting as a critical effector of C/EBPβ. Our results demonstrate that the differential regulation of antagonistic TSC22D1 variants is required for the establishment of OIS and suggest distinct contributions of TSC22 family members to the progression of BRAFE600-driven neoplasia.

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