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

Joao Passos, Glyn Nelson, Chunfang Wang, Torsten Richter, Cedric Simillion, Carole J. Proctor, Satomi Miwa, Sharon Olijslagers, Jennifer Hallinan, Anil Wipat, Gabriele Saretzki, Karl Lenhard Rudolph, Tom B.L. Kirkwood, Thomas Von Zglinicki

Research output: Contribution to journalArticle

380 Citations (Scopus)

Abstract

Cellular senescencethe permanent arrest of cycling in normally proliferating cells such as fibroblastscontributes 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.

Original languageEnglish (US)
Article number347
JournalMolecular Systems Biology
Volume6
DOIs
StatePublished - Feb 26 2010
Externally publishedYes

Fingerprint

Senescence
Cell Aging
DNA damage
DNA Damage
Reactive Oxygen Species
Oxygen
DNA
Damage
Feedback
Necessary
Tissue homeostasis
reactive oxygen species
Cell
Mitogen-Activated Protein Kinase 14
Genes
Gene
Homeostasis
Checkpoint
Stochastic Modeling
Cycling

Keywords

  • Aging
  • Cell senescence
  • DNA damage foci
  • Mitochondria
  • Reactive oxygen

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Agricultural and Biological Sciences(all)
  • Applied Mathematics

Cite this

Passos, J., Nelson, G., Wang, C., Richter, T., Simillion, C., Proctor, C. J., ... Von Zglinicki, T. (2010). Feedback between p21 and reactive oxygen production is necessary for cell senescence. Molecular Systems Biology, 6, [347]. https://doi.org/10.1038/msb.2010.5

Feedback between p21 and reactive oxygen production is necessary for cell senescence. / Passos, Joao; 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.

In: Molecular Systems Biology, Vol. 6, 347, 26.02.2010.

Research output: Contribution to journalArticle

Passos, J, Nelson, G, Wang, C, Richter, T, Simillion, C, Proctor, CJ, Miwa, S, Olijslagers, S, Hallinan, J, Wipat, A, Saretzki, G, Rudolph, KL, Kirkwood, TBL & Von Zglinicki, T 2010, 'Feedback between p21 and reactive oxygen production is necessary for cell senescence', Molecular Systems Biology, vol. 6, 347. https://doi.org/10.1038/msb.2010.5
Passos, Joao ; 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. / Feedback between p21 and reactive oxygen production is necessary for cell senescence. In: Molecular Systems Biology. 2010 ; Vol. 6.
@article{53dca3a95844437b8f334a1f15cf4e38,
title = "Feedback between p21 and reactive oxygen production is necessary for cell senescence",
abstract = "Cellular senescencethe permanent arrest of cycling in normally proliferating cells such as fibroblastscontributes 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.",
keywords = "Aging, Cell senescence, DNA damage foci, Mitochondria, Reactive oxygen",
author = "Joao Passos and Glyn Nelson and Chunfang Wang and Torsten Richter and Cedric Simillion and Proctor, {Carole J.} and Satomi Miwa and Sharon Olijslagers and Jennifer Hallinan and Anil Wipat and Gabriele Saretzki and Rudolph, {Karl Lenhard} and Kirkwood, {Tom B.L.} and {Von Zglinicki}, Thomas",
year = "2010",
month = "2",
day = "26",
doi = "10.1038/msb.2010.5",
language = "English (US)",
volume = "6",
journal = "Molecular Systems Biology",
issn = "1744-4292",
publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Feedback between p21 and reactive oxygen production is necessary for cell senescence

AU - Passos, Joao

AU - Nelson, Glyn

AU - Wang, Chunfang

AU - Richter, Torsten

AU - Simillion, Cedric

AU - Proctor, Carole J.

AU - Miwa, Satomi

AU - Olijslagers, Sharon

AU - Hallinan, Jennifer

AU - Wipat, Anil

AU - Saretzki, Gabriele

AU - Rudolph, Karl Lenhard

AU - Kirkwood, Tom B.L.

AU - Von Zglinicki, Thomas

PY - 2010/2/26

Y1 - 2010/2/26

N2 - Cellular senescencethe permanent arrest of cycling in normally proliferating cells such as fibroblastscontributes 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.

AB - Cellular senescencethe permanent arrest of cycling in normally proliferating cells such as fibroblastscontributes 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.

KW - Aging

KW - Cell senescence

KW - DNA damage foci

KW - Mitochondria

KW - Reactive oxygen

UR - http://www.scopus.com/inward/record.url?scp=77149164811&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77149164811&partnerID=8YFLogxK

U2 - 10.1038/msb.2010.5

DO - 10.1038/msb.2010.5

M3 - Article

C2 - 20160708

AN - SCOPUS:77149164811

VL - 6

JO - Molecular Systems Biology

JF - Molecular Systems Biology

SN - 1744-4292

M1 - 347

ER -