Mitogenic signalling and the p16INK4a–Rb pathway cooperate to enforce irreversible cellular senescence

@article{Takahashi2006MitogenicSA,
  title={Mitogenic signalling and the p16INK4a–Rb pathway cooperate to enforce irreversible cellular senescence},
  author={Akiko Takahashi and Naoko Ohtani and Kimi Yamakoshi and S Iida and Hidetoshi Tahara and Keiko Nakayama and Keiichi I. Nakayama and Toshinori Ide and Hideyuki Saya and Eiji Hara},
  journal={Nature Cell Biology},
  year={2006},
  volume={8},
  pages={1291-1297}
}
The p16INK4a cyclin-dependent kinase inhibitor has a key role in establishing stable G1 cell-cycle arrest through activating the retinoblastoma (Rb) tumour suppressor protein pRb in cellular senescence. Here, we show that the p16INK4a /Rb-pathway also cooperates with mitogenic signals to induce elevated intracellular levels of reactive oxygen species (ROS), thereby activating protein kinase Cδ (PKCδ) in human senescent cells. Importantly, once activated by ROS, PKCδ promotes further generation… Expand
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References

SHOWING 1-10 OF 34 REFERENCES
Opposing effects of Ets and Id proteins on p16INK4a expression during cellular senescence
TLDR
A role is demonstrated for the Ets1 and Ets2 transcription factors based on their ability to activate the p16INK4a promoter through an ETS-binding site and their patterns of expression during the lifespan of human diploid fibroblasts. Expand
Mitogen Stimulation Cooperates with Telomere Shortening To Activate DNA Damage Responses and Senescence Signaling
TLDR
This study shows that replicative senescence signaling operates at a low level in cells with shortened telomeres but becomes fully activated when cells are stimulated to enter the cell cycle by mitogen stimulation. Expand
p16INK4a can initiate an autonomous senescence program
TLDR
It is demonstrated that a sustained period of p16INK4a expression is sufficient in this setting to impose a durable block to cell proliferation and that this state becomes independent of p 16INK 4a expression, hypophosphorylation of pRB, or a strict G1 arrest. Expand
Tumor suppressor WARTS ensures genomic integrity by regulating both mitotic progression and G1 tetraploidy checkpoint function
TLDR
It is shown that WARTS is activated during mitosis in mammalian cells, and that overexpression of a kinase-inactive WARTS in Rat1 fibroblasts significantly induced mitotic delay. Expand
Mitogenic Signaling Mediated by Oxidants in Ras-Transformed Fibroblasts
TLDR
H-RasV12-induced transformation can lead to the production of ·O2− through one or more pathways involving a flavoprotein and Rac1, suggesting a possible mechanism for the effects of antioxidants against Ras-induced cellular transformation. Expand
Reversal of human cellular senescence: roles of the p53 and p16 pathways
TLDR
The results indicate that the senescence response to telomere dysfunction is reversible and is maintained primarily by p53, however, p16 provides a dominant second barrier to the unlimited growth of human cells. Expand
Protein Kinase Cδ Blocks Immediate-Early Gene Expression in Senescent Cells by Inactivating Serum Response Factor
TLDR
Observations support the idea that the coordinate transcriptional inhibition of several growth-associated genes by PKCδ contributes to the senescent phenotype. Expand
Ras Proteins Induce Senescence by Altering the Intracellular Levels of Reactive Oxygen Species*
TLDR
It is suggested that in normal diploid cells, Ras proteins regulate oxidant production and that a rise in intracellular H2O2 represents a critical signal mediating replicative senescence. Expand
Loss of Proliferative Capacity and Induction of Senescence in Oxidatively Stressed Human Fibroblasts*
TLDR
Changes in levels of key proteins involved in cell cycle regulation, DNA replication, and stress resistance in senescing human fibroblasts following oxidative stress suggest that loss of proliferative capacity in oxidatively stressed cells is a multistep process regulated by time-dependent molecular events. Expand
Regulation of growth arrest in senescence: Telomere damage is not the end of the story
TLDR
The current literature is reviewed to propose a model how independent signals activate distinct signaling pathways to regulate p21 and p16(INK4a) levels in senescent cells. Expand
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