Open AccessFeedback between p21 and reactive oxygen production is necessary for cell senescence
Author(s) -
Passos João F,
Nelson Glyn,
Wang Chunfang,
Richter Torsten,
Simillion Cedric,
Proctor Carole J,
Miwa Satomi,
Olijslagers Sharon,
Hallinan Jennifer,
Wipat Anil,
Saretzki Gabriele,
Rudolph Karl Lenhard,
Kirkwood Tom B L,
von Zglinicki Thomas
Publication year - 2010
Publication title -
molecular systems biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 8.523
H-Index - 148
ISSN - 1744-4292
DOI - 10.1038/msb.2010.5
Subject(s) - biology , microbiology and biotechnology , senescence , dna damage , interactome , reactive oxygen species , phenotype , genetics , gene , dna
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.