Nrf2-Mediated Fibroblast Reprogramming Drives Cellular Senescence by Targeting the Matrisome
| Autor: | Jürgen Brinckmann, Michael Cangkrama, Serena Grossi, Dimitris Kletsas, Jörn Dengjel, Paul Hiebert, Mateusz S. Wietecha, Heiko Steenbock, Hans-Dietmar Beer, Eric Haertel, Michael Stumpe, Eleni Mavrogonatou, Peter Angel, Sabine Werner |
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| Přispěvatelé: | University of Zurich, Hiebert, Paul |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Senescence Carcinogenesis NF-E2-Related Factor 2 610 Medicine & health Biology medicine.disease_cause digestive system environment and public health General Biochemistry Genetics and Molecular Biology Antioxidants 1309 Developmental Biology 1307 Cell Biology Extracellular matrix 03 medical and health sciences Mice 1300 General Biochemistry Genetics and Molecular Biology cancer-associated fibroblast Fibroblast Nrf2 Wound healing Cancer SASP 1312 Molecular Biology medicine Animals Molecular Biology Transcription factor Cellular Senescence Cell Proliferation Skin Wound Healing 10177 Dermatology Clinic Cell Biology respiratory system Fibroblasts Cellular Reprogramming 3. Good health Cell biology Extracellular Matrix Oxidative Stress 030104 developmental biology medicine.anatomical_structure Gene Expression Regulation Chromatin immunoprecipitation Reprogramming Developmental Biology |
| Zdroj: | Developmental Cell, 46 (2) |
| ISSN: | 1878-1551 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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