• Open Access

High levels of oncomiR-21 contribute to the senescence-induced growth arrest in normal human cells and its knock-down increases the replicative lifespan

Authors

  • Hanna Dellago,

    1. Department of Biotechnology, BOKU-VIBT University of Natural Resources and Life Sciences Vienna, Vienna, Austria
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    • Those authors contributed equally
  • Barbara Preschitz-Kammerhofer,

    1. Department of Biotechnology, BOKU-VIBT University of Natural Resources and Life Sciences Vienna, Vienna, Austria
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    • Those authors contributed equally
  • Lucia Terlecki-Zaniewicz,

    1. Department of Biotechnology, BOKU-VIBT University of Natural Resources and Life Sciences Vienna, Vienna, Austria
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  • Carina Schreiner,

    1. Department of Biotechnology, BOKU-VIBT University of Natural Resources and Life Sciences Vienna, Vienna, Austria
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  • Klaus Fortschegger,

    1. CCRI - Children's Cancer Research Institute, Vienna, Austria
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  • Martina W.-F. Chang,

    1. Department of Biotechnology, BOKU-VIBT University of Natural Resources and Life Sciences Vienna, Vienna, Austria
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  • Matthias Hackl,

    1. Department of Biotechnology, BOKU-VIBT University of Natural Resources and Life Sciences Vienna, Vienna, Austria
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  • Rossella Monteforte,

    1. Department of Biotechnology, BOKU-VIBT University of Natural Resources and Life Sciences Vienna, Vienna, Austria
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  • Harald Kühnel,

    1. Institute of Physiology, Pathophysiology and Biophysics, Department of Biomedical Sciences, University of Veterinary Medicine Vienna, Vienna, Austria
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  • Markus Schosserer,

    1. Department of Biotechnology, BOKU-VIBT University of Natural Resources and Life Sciences Vienna, Vienna, Austria
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  • Florian Gruber,

    1. Department of Dermatology, Medical University of Vienna, Vienna, Austria
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  • Erwin Tschachler,

    1. Department of Dermatology, Medical University of Vienna, Vienna, Austria
    2. C.E.R.I.E.S. - Centre de Recherches et d'Investigations Epidermiques et Sensorielles, Neuilly-sur-Seine, France
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  • Marcel Scheideler,

    1. Institute for Genomics and Bioinformatics, Graz University of Technology, Graz, Austria
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  • Regina Grillari-Voglauer,

    1. Department of Biotechnology, BOKU-VIBT University of Natural Resources and Life Sciences Vienna, Vienna, Austria
    2. Evercyte GmbH, Vienna, Austria
    3. Austrian Centre of Industrial Biotechnology (ACIB GmbH), Vienna, Austria
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  • Johannes Grillari,

    Corresponding author
    1. Evercyte GmbH, Vienna, Austria
    • Department of Biotechnology, BOKU-VIBT University of Natural Resources and Life Sciences Vienna, Vienna, Austria
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  • Matthias Wieser

    1. Department of Biotechnology, BOKU-VIBT University of Natural Resources and Life Sciences Vienna, Vienna, Austria
    2. Austrian Centre of Industrial Biotechnology (ACIB GmbH), Vienna, Austria
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Correspondence

Johannes Grillari, Department of Biotechnology, BOKU - University of Natural Resources and Applied Life Sciences Vienna, Muthgasse 18, 1190 Vienna, Austria. Tel: +43 1 47654 6230; fax +43 1 3697615; e-mail: johannes.grillari@boku.ac.at

Summary

Cellular senescence of normal human cells has by now far exceeded its initial role as a model system for aging research. Many reports show the accumulation of senescent cells in vivo, their effect on their microenvironment and its double-edged role as tumour suppressor and promoter. Importantly, removal of senescent cells delays the onset of age-associated diseases in mouse model systems. To characterize the role of miRNAs in cellular senescence of endothelial cells, we performed miRNA arrays from HUVECs of five different donors. Twelve miRNAs, comprising hsa-miR-23a, hsa-miR-23b, hsa-miR-24, hsa-miR-27a, hsa-miR-29a, hsa-miR-31, hsa-miR-100, hsa-miR-193a, hsa-miR-221, hsa-miR-222 and hsa-let-7i are consistently up-regulated in replicatively senescent cells. Surprisingly, also miR-21 was found up-regulated by replicative and stress-induced senescence, despite being described as oncogenic. Transfection of early passage endothelial cells with miR-21 resulted in lower angiogenesis, and less cell proliferation mirrored by up-regulation of p21CIP1 and down-regulation of CDK2. These two cell-cycle regulators are indirectly regulated by miR-21 via its validated direct targets NFIB (Nuclear factor 1 B-type), a transcriptional inhibitor of p21CIP1, and CDC25A, which regulates CDK2 activity by dephosphorylation. Knock-down of either NFIB or CDC25A shows a phenocopy of over-expressing miR-21 in regard to cell-cycle arrest. Finally, miR-21 over-epxression reduces the replicative lifespan, while stable knock-down by sponges extends the replicative lifespan of endothelial cells. Therefore, we propose that miR-21 is the first miRNA that upon its knock-down extends the replicative lifespan of normal human cells.

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