Feedback between p21 and reactive oxygen production is necessary for cell senescence
Abstract Cellular senescence—the permanent arrest of cycling in normally proliferating cells such as fibroblasts—contributes both to age‐related loss of mammalian tissue homeostasis and acts as a tumour suppressor mechanism. The pathways leading to establishment of senescence are proving to be more...
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| Format: | Article |
| Language: | English |
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Springer Nature
2010-02-01
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| Series: | Molecular Systems Biology |
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| Online Access: | https://doi.org/10.1038/msb.2010.5 |
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| author | João F Passos Glyn Nelson Chunfang Wang Torsten Richter Cedric Simillion Carole J Proctor Satomi Miwa Sharon Olijslagers Jennifer Hallinan Anil Wipat Gabriele Saretzki Karl Lenhard Rudolph Tom B L Kirkwood Thomas von Zglinicki |
| author_facet | João F Passos Glyn Nelson Chunfang Wang Torsten Richter Cedric Simillion Carole J Proctor Satomi Miwa Sharon Olijslagers Jennifer Hallinan Anil Wipat Gabriele Saretzki Karl Lenhard Rudolph Tom B L Kirkwood Thomas von Zglinicki |
| author_sort | João F Passos |
| collection | DOAJ |
| description | Abstract Cellular senescence—the permanent arrest of cycling in normally proliferating cells such as fibroblasts—contributes both to age‐related loss of mammalian tissue homeostasis and acts as a tumour suppressor mechanism. The pathways leading to establishment of senescence are proving to be more complex than was previously envisaged. Combining in‐silico interactome analysis and functional target gene inhibition, stochastic modelling and live cell microscopy, we show here that there exists a dynamic feedback loop that is triggered by a DNA damage response (DDR) and, which after a delay of several days, locks the cell into an actively maintained state of ‘deep’ cellular senescence. The essential feature of the loop is that long‐term activation of the checkpoint gene CDKN1A (p21) induces mitochondrial dysfunction and production of reactive oxygen species (ROS) through serial signalling through GADD45‐MAPK14(p38MAPK)‐GRB2‐TGFBR2‐TGFβ. These ROS in turn replenish short‐lived DNA damage foci and maintain an ongoing DDR. We show that this loop is both necessary and sufficient for the stability of growth arrest during the establishment of the senescent phenotype. |
| format | Article |
| id | doaj-art-c7825abd71494da28dc87edfd7c598df |
| institution | OA Journals |
| issn | 1744-4292 |
| language | English |
| publishDate | 2010-02-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | Molecular Systems Biology |
| spelling | doaj-art-c7825abd71494da28dc87edfd7c598df2025-08-20T02:18:35ZengSpringer NatureMolecular Systems Biology1744-42922010-02-016111410.1038/msb.2010.5Feedback between p21 and reactive oxygen production is necessary for cell senescenceJoão F Passos0Glyn Nelson1Chunfang Wang2Torsten Richter3Cedric Simillion4Carole J Proctor5Satomi Miwa6Sharon Olijslagers7Jennifer Hallinan8Anil Wipat9Gabriele Saretzki10Karl Lenhard Rudolph11Tom B L Kirkwood12Thomas von Zglinicki13Ageing Research Laboratories, Institute for Ageing and Health, Newcastle UniversityAgeing Research Laboratories, Institute for Ageing and Health, Newcastle UniversityAgeing Research Laboratories, Institute for Ageing and Health, Newcastle UniversityAgeing Research Laboratories, Institute for Ageing and Health, Newcastle UniversityCentre for Integrated Systems Biology of Ageing and Nutrition, Institute for Ageing and Health, Newcastle UniversityAgeing Research Laboratories, Institute for Ageing and Health, Newcastle UniversityAgeing Research Laboratories, Institute for Ageing and Health, Newcastle UniversityAgeing Research Laboratories, Institute for Ageing and Health, Newcastle UniversityCentre for Integrated Systems Biology of Ageing and Nutrition, Institute for Ageing and Health, Newcastle UniversityCentre for Integrated Systems Biology of Ageing and Nutrition, Institute for Ageing and Health, Newcastle UniversityCentre for Integrated Systems Biology of Ageing and Nutrition, Institute for Ageing and Health, Newcastle UniversityDepartment of Molecular Medicine and Max‐Planck Research Group on Stem Cell Aging, University of UlmAgeing Research Laboratories, Institute for Ageing and Health, Newcastle UniversityAgeing Research Laboratories, Institute for Ageing and Health, Newcastle UniversityAbstract Cellular senescence—the permanent arrest of cycling in normally proliferating cells such as fibroblasts—contributes both to age‐related loss of mammalian tissue homeostasis and acts as a tumour suppressor mechanism. The pathways leading to establishment of senescence are proving to be more complex than was previously envisaged. Combining in‐silico interactome analysis and functional target gene inhibition, stochastic modelling and live cell microscopy, we show here that there exists a dynamic feedback loop that is triggered by a DNA damage response (DDR) and, which after a delay of several days, locks the cell into an actively maintained state of ‘deep’ cellular senescence. The essential feature of the loop is that long‐term activation of the checkpoint gene CDKN1A (p21) induces mitochondrial dysfunction and production of reactive oxygen species (ROS) through serial signalling through GADD45‐MAPK14(p38MAPK)‐GRB2‐TGFBR2‐TGFβ. These ROS in turn replenish short‐lived DNA damage foci and maintain an ongoing DDR. We show that this loop is both necessary and sufficient for the stability of growth arrest during the establishment of the senescent phenotype.https://doi.org/10.1038/msb.2010.5agingcell senescenceDNA damage focimitochondriareactive oxygen |
| spellingShingle | João F Passos Glyn Nelson Chunfang Wang Torsten Richter Cedric Simillion Carole J Proctor Satomi Miwa Sharon Olijslagers Jennifer Hallinan Anil Wipat Gabriele Saretzki Karl Lenhard Rudolph Tom B L Kirkwood Thomas von Zglinicki Feedback between p21 and reactive oxygen production is necessary for cell senescence Molecular Systems Biology aging cell senescence DNA damage foci mitochondria reactive oxygen |
| title | Feedback between p21 and reactive oxygen production is necessary for cell senescence |
| title_full | Feedback between p21 and reactive oxygen production is necessary for cell senescence |
| title_fullStr | Feedback between p21 and reactive oxygen production is necessary for cell senescence |
| title_full_unstemmed | Feedback between p21 and reactive oxygen production is necessary for cell senescence |
| title_short | Feedback between p21 and reactive oxygen production is necessary for cell senescence |
| title_sort | feedback between p21 and reactive oxygen production is necessary for cell senescence |
| topic | aging cell senescence DNA damage foci mitochondria reactive oxygen |
| url | https://doi.org/10.1038/msb.2010.5 |
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