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Feedback between p21 and reactive oxygen production is necessary for cell senescence

Lookup NU author(s): Dr Joao Passos, Dr Glyn Nelson, Dr Cedric Simillion, Dr Carole Proctor, Dr Satomi Miwa, Dr Sharon Olijslagers, Dr Jennifer Hallinan, Professor Anil Wipat, Dr Gabriele Saretzki, Emeritus Professor Thomas Kirkwood, Professor Thomas von Zglinicki

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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-TGF beta. 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. Molecular Systems Biology 6: 347; published online 16 February 2010; doi:10.1038/msb.2010.5


Publication metadata

Author(s): Passos JF, Nelson G, Wang CF, Richter T, Simillion C, Proctor CJ, Miwa S, Olijslagers S, Hallinan J, Wipat A, Saretzki G, Rudolph KL, Kirkwood TBL, von Zglinicki T

Publication type: Article

Publication status: Published

Journal: Molecular Systems Biology

Year: 2010

Volume: 6

Issue: 1

Print publication date: 16/02/2010

ISSN (print): 1744-4292

ISSN (electronic):

Publisher: Nature Publishing Group

URL: http://dx.doi.org/10.1038/msb.2010.5

DOI: 10.1038/msb.2010.5


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