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MicroRNA-16 feedback loop with p53 and Wip1 can regulate cell fate determination between apoptosis and senescence in

Maria Vitória C Issler1, José Carlos M Mombach1

  • 1Department of Physics, Universidade Federal de Santa Maria, Santa Maria, Rio Grande do Sul, Brazil.

Plos One
|October 3, 2017
PubMed

Insights

DNA damage triggers cell fate decisions like apoptosis or senescence. A new model shows the p53 pathway

Area of Science:

  • Cellular biology and molecular mechanisms of DNA damage response.
  • Systems biology and computational modeling of cellular pathways.

Background:

  • Cell fate determination is crucial in biosciences, with DNA damage response pathways playing a key role.
  • The p53 pathway exhibits switch-like dynamics, leading to distinct cellular outcomes like apoptosis or senescence.
  • MicroRNA 16-1 (miR-16) is implicated in regulating the balance between apoptosis and senescence phenotypes in cancer cells.

Purpose of the Study:

  • To develop a logical model of the G1/S checkpoint in DNA damage response.
  • To investigate the influence of miR-16 on cell fate decisions.
  • To analyze how different levels of DNA damage affect cellular phenotypes.

Main Methods:

  • Development of a logical model for the G1/S checkpoint.
  • Inclusion of DNA damage levels and miR-16 influence via a positive feedback loop with p53 and Wip1.
  • Comparison of model predictions with experimental observations of cellular phenotypes.

Main Results:

  • The model successfully reproduces oscillatory patterns for low DNA damage (DNA repair) and apoptotic/senescent states for high DNA damage.
  • Negative feedback loops involving p53 and Mdm2 regulate low-damage responses, while a positive p53/Wip1/miR-16 feedback loop governs high-damage responses.
  • The positive feedback loop leads to stochastic (bistable) determination of senescent and apoptotic phenotypes, which can be controlled by miR-16 expression levels.

Conclusions:

  • The developed logical model accurately represents cell fate regulation under DNA damage.
  • The p53/Wip1/miR-16 positive feedback loop is critical for determining apoptosis versus senescence.
  • Modulating miR-16 expression offers a potential strategy for controlling cell fate decisions in response to DNA damage.

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