Dataset Information

Passos2010_DNAdamage_CellularSenescence

ABSTRACT: This is the model described in: Feedback between p21 and reactive oxygen production is necessary for cell senescence. Passos JF, Nelson G, Wang C, Richter T, Simillion C, Proctor CJ, Miwa S, Olijslagers S, Hallinan J, Wipat A, Saretzki G, Rudolph KL, Kirkwood TB, von Zglinicki T. ;Mol Sys Biol2010;6:347. Epub 2010 Feb 16. PMID:20160708 doi:10.1038/msb.2010.5; 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-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. This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2010 The BioModels.net Team.For more information see the terms of use.To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.

SUBMITTER: Carole Proctor

PROVIDER: BIOMD0000000287 | BioModels | 2024-09-02

REPOSITORIES: BioModels

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			Action	DRS
	BIOMD0000000287?filename=BIOMD0000000287-biopax2.owl	Owl
	BIOMD0000000287?filename=BIOMD0000000287-biopax3.owl	Owl
	BIOMD0000000287?filename=BIOMD0000000287-matlab.m	Other
	BIOMD0000000287?filename=BIOMD0000000287.m	Other
	BIOMD0000000287?filename=BIOMD0000000287.ode	Other

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

Passos João F JF 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

Molecular systems biology 20100216

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 ...[more]

PMID: 20160708

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