Hiebert, Paul Wietecha, Mateusz S. Cangkrama, Michael Haertel, Eric Mavrogonatou, Eleni Stumpe, Michael Steenbock, Heiko Grossi, Serena Beer, Hans-Dietmar Angel, Peter Brinckmann, Jürgen Kletsas, Dimitris Dengjel, Jörn Werner, Sabine 2018-07-16 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. application/pdf https://folia.unifr.ch/global/documents/307353 https://folia.unifr.ch/documents/307353/files/den_nmf.pdf https://folia.unifr.ch/documents/307353/files/den_nmf_sm.pdf eng info:eu-repo/semantics/altIdentifier/doi/10.1016/j.devcel.2018.06.012 info:eu-repo/semantics/openAccess License undefined Developmental Cell. - 2018, vol. 46, no. 2, p. 145-161.e10 info:eu-repo/classification/udc/57 Nrf2-mediated fibroblast reprogramming drives cellular senescence by targeting the matrisome http://purl.org/coar/resource_type/c_6501