Journal article
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Nrf2-mediated fibroblast reprogramming drives cellular senescence by targeting the matrisome
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Hiebert, Paul
Institute of Molecular Health Sciences, Department of Biology, Swiss Federal Institute of Technology (ETH) Zurich, Switzerland
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Wietecha, Mateusz S.
Institute of Molecular Health Sciences, Department of Biology, Swiss Federal Institute of Technology (ETH) Zurich, Switzerland
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Cangkrama, Michael
Institute of Molecular Health Sciences, Department of Biology, Swiss Federal Institute of Technology (ETH) Zurich, Switzerland
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Haertel, Eric
Institute of Molecular Health Sciences, Department of Biology, Swiss Federal Institute of Technology (ETH) Zurich, Switzerland
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Mavrogonatou, Eleni
Laboratory of Cell Proliferation and Ageing, Institute of Biosciences and Applications, National Centre for Scientific Research ?Demokritos?, Athens, Greece
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Stumpe, Michael
Department of Biology, University of Fribourg, Switzerland
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Steenbock, Heiko
Institute of Virology and Cell Biology, University of Lübeck, Germany
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Grossi, Serena
Faculty of Medicine, University of Zürich, Switzerland
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Beer, Hans-Dietmar
Faculty of Medicine, University of Zürich, Switzerland
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Angel, Peter
Division of Signal Transduction and Growth Control, German Cancer Research Center (DKFZ), Heidelberg, Germany
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Brinckmann, Jürgen
Institute of Virology and Cell Biology, University of Lübeck, Germany - Department of Dermatology, University of Lübeck, Germany
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Kletsas, Dimitris
Laboratory of Cell Proliferation and Ageing, Institute of Biosciences and Applications, National Centre for Scientific Research ?Demokritos?, Athens, Greece
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Dengjel, Jörn
Department of Biology, University of Fribourg, Switzerland
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Werner, Sabine
Institute of Molecular Health Sciences, Department of Biology, Swiss Federal Institute of Technology (ETH) Zurich, Switzerland
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Published in:
- Developmental Cell. - 2018, vol. 46, no. 2, p. 145-161.e10
English
Nrf2 is a key regulator of the antioxidant defense system, and pharmacological Nrf2 activation is a promising strategy for cancer prevention and promotion of tissue repair. Here we show, however, that activation of Nrf2 in fibroblasts induces cellular senescence. Using a combination of transcriptomics, matrix proteomics, chromatin immunoprecipitation and bioinformatics we demonstrate that fibroblasts with activated Nrf2 deposit a senescence-promoting matrix, with plasminogen activator inhibitor-1 being a key inducer of the senescence program. In vivo, activation of Nrf2 in fibroblasts promoted re-epithelialization of skin wounds, but also skin tumorigenesis. The pro-tumorigenic activity is of general relevance, since Nrf2 activation in skin fibroblasts induced the expression of genes characteristic for cancer-associated fibroblasts from different mouse and human tumors. Therefore, activated Nrf2 qualifies as a marker of the cancer-associated fibroblast phenotype. These data highlight the bright and the dark sides of Nrf2 and the need for time-controlled activation of this transcription factor.
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Faculty
- Faculté des sciences et de médecine
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Department
- Département de Biologie
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Language
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Classification
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Biological sciences
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License
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License undefined
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Identifiers
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Persistent URL
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https://folia.unifr.ch/unifr/documents/307353
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