Feedback between p21 and reactive oxygen production is necessary for cell senescence.
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-TGFbeta. 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.
Passos
João F
JF
Ageing Research Laboratories, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, UK.
Nelson
Glyn
G
Wang
Chunfang
C
Richter
Torsten
T
Simillion
Cedric
C
Proctor
Carole J
CJ
Miwa
Satomi
S
Olijslagers
Sharon
S
Hallinan
Jennifer
J
Wipat
Anil
A
Saretzki
Gabriele
G
Rudolph
Karl Lenhard
KL
Kirkwood
Tom B L
TB
von Zglinicki
Thomas
T
D002453:Cell Cycle; D016922:Cellular Senescence / Q000502:physiology*; D003198:Computer Simulation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis* / Q000235:genetics; D004249:DNA Damage; D025461:Feedback, Physiological / Q000502:physiology; D006651:Histocytochemistry; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D008954:Models, Biological; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013269:Stochastic Processes; D049490:Systems Biology / Q000379:methods
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D017382:Reactive Oxygen Species