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

ACCESS DATA

Dataset's files

Source:

			Action	DRS
	BIOMD0000000287?filename=BIOMD0000000287-biopax2.owl	Owl
	BIOMD0000000287?filename=BIOMD0000000287-biopax3.owl	Owl
	BIOMD0000000287?filename=BIOMD0000000287.m	Other
	BIOMD0000000287?filename=BIOMD0000000287.pdf	Pdf
	BIOMD0000000287?filename=BIOMD0000000287.png	Other

Items per page:

1 - 5 of 11

Publications

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

Similar Datasets

Project description:DallePazze2014 - Cellular senescene-induced mitochondrial dysfunction This model is described in the article: Dynamic modelling of pathways to cellular senescence reveals strategies for targeted interventions. Dalle Pezze P, Nelson G, Otten EG, Korolchuk VI, Kirkwood TB, von Zglinicki T, Shanley DP. PLoS Comput. Biol. 2014 Aug; 10(8): e1003728 Abstract: Cellular senescence, a state of irreversible cell cycle arrest, is thought to help protect an organism from cancer, yet also contributes to ageing. The changes which occur in senescence are controlled by networks of multiple signalling and feedback pathways at the cellular level, and the interplay between these is difficult to predict and understand. To unravel the intrinsic challenges of understanding such a highly networked system, we have taken a systems biology approach to cellular senescence. We report a detailed analysis of senescence signalling via DNA damage, insulin-TOR, FoxO3a transcription factors, oxidative stress response, mitochondrial regulation and mitophagy. We show in silico and in vitro that inhibition of reactive oxygen species can prevent loss of mitochondrial membrane potential, whilst inhibition of mTOR shows a partial rescue of mitochondrial mass changes during establishment of senescence. Dual inhibition of ROS and mTOR in vitro confirmed computational model predictions that it was possible to further reduce senescence-induced mitochondrial dysfunction and DNA double-strand breaks. However, these interventions were unable to abrogate the senescence-induced mitochondrial dysfunction completely, and we identified decreased mitochondrial fission as the potential driving force for increased mitochondrial mass via prevention of mitophagy. Dynamic sensitivity analysis of the model showed the network stabilised at a new late state of cellular senescence. This was characterised by poor network sensitivity, high signalling noise, low cellular energy, high inflammation and permanent cell cycle arrest suggesting an unsatisfactory outcome for treatments aiming to delay or reverse cellular senescence at late time points. Combinatorial targeted interventions are therefore possible for intervening in the cellular pathway to senescence, but in the cases identified here, are only capable of delaying senescence onset. This model is hosted on BioModels Database and identified by: BIOMD0000000582. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Project description:Kollarovic2016 - Cell fate decision at G1-S transition This model is described in the article: To senesce or not to senesce: how primary human fibroblasts decide their cell fate after DNA damage. Kollarovic G, Studencka M, Ivanova L, Lauenstein C, Heinze K, Lapytsko A, Talemi SR, Figueiredo AS, Schaber J. Aging (Albany NY) 2016 Jan; Abstract: Excessive DNA damage can induce an irreversible cell cycle arrest, called senescence, which is generally perceived as an important tumour-suppressor mechanism. However, it is unclear how cells decide whether to senesce or not after DNA damage. By combining experimental data with a parameterized mathematical model we elucidate this cell fate decision at the G1-S transition. Our model provides a quantitative and conceptually new understanding of how human fibroblasts decide whether DNA damage is beyond repair and senesce. Model and data imply that the G1-S transition is regulated by a bistable hysteresis switch with respect to Cdk2 activity, which in turn is controlled by the Cdk2/p21 ratio rather than cyclin abundance. We experimentally confirm the resulting predictions that to induce senescence i) in healthy cells both high initial and elevated background DNA damage are necessary and sufficient, and ii) in already damaged cells much lower additional DNA damage is sufficient. Our study provides a mechanistic explanation of a) how noise in protein abundances allows cells to overcome the G1-S arrest even with substantial DNA damage, potentially leading to neoplasia, and b) how accumulating DNA damage with age increasingly sensitizes cells for senescence. This model is hosted on BioModels Database and identified by: BIOMD0000000632. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Project description:Barr2017 - Dynamics of p21 in hTert-RPE1 cells This deteministic model reveals that a bistable switch created by Cdt2, promotes irreversible S-phase entry by keeping p21 levels low, prevents premature S-phase exit upon DNA damage This model is described in the article: DNA damage during S-phase mediates the proliferation-quiescence decision in the subsequent G1 via p21 expression. Barr AR, Cooper S, Heldt FS, Butera F, Stoy H, Mansfeld J, Novák B, Bakal C. Nat Commun 2017 Mar; 8: 14728 Abstract: Following DNA damage caused by exogenous sources, such as ionizing radiation, the tumour suppressor p53 mediates cell cycle arrest via expression of the CDK inhibitor, p21. However, the role of p21 in maintaining genomic stability in the absence of exogenous DNA-damaging agents is unclear. Here, using live single-cell measurements of p21 protein in proliferating cultures, we show that naturally occurring DNA damage incurred over S-phase causes p53-dependent accumulation of p21 during mother G2- and daughter G1-phases. High p21 levels mediate G1 arrest via CDK inhibition, yet lower levels have no impact on G1 progression, and the ubiquitin ligases CRL4Cdt2 and SCFSkp2 couple to degrade p21 prior to the G1/S transition. Mathematical modelling reveals that a bistable switch, created by CRL4Cdt2, promotes irreversible S-phase entry by keeping p21 levels low, preventing premature S-phase exit upon DNA damage. Thus, we characterize how p21 regulates the proliferation-quiescence decision to maintain genomic stability. This model is hosted on BioModels Database and identified by: BIOMD0000000660. To cite BioModels Database, please use: Chelliah V et al. BioModels: ten-year anniversary. Nucl. Acids Res. 2015, 43(Database issue):D542-8. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.