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In Vivo Biosensor Tracks Non-apoptotic Caspase Activity in Drosophila
Published on: November 27, 2016
Coordination between cell proliferation and apoptosis after DNA damage in Drosophila
Mireya Ruiz-Losada1, Raul González1,2, Ana Peropadre3
1Centro de Biología Molecular "Severo Ochoa", CSIC-UAM, C/Nicolás Cabrera 1, 28049, Madrid, Spain.
Abstract:
Exposure to genotoxic stress promotes cell cycle arrest and DNA repair or apoptosis. These "life" or "death" cell fate decisions often rely on the activity of the tumor suppressor gene p53. Therefore, the precise regulation of p53 is essential to maintain tissue homeostasis and to prevent cancer development. However, how cell cycle progression has an impact on p53 cell fate decision-making is mostly unknown. In this work, we demonstrate that Drosophila p53 proapoptotic activity can be impacted by the G2/M kinase Cdk1. We find that cell cycle arrested or endocycle-induced cells are refractory to ionizing radiation-induced apoptosis. We show that p53 binding to the regulatory elements of the proapoptotic genes and its ability to activate their expression is compromised in experimentally arrested cells. Our results indicate that p53 genetically and physically interacts with Cdk1 and that p53 proapoptotic role is regulated by the cell cycle status of the cell. We propose a model in which cell cycle progression and p53 proapoptotic activity are molecularly connected to coordinate the appropriate response after DNA damage.
Insights
Cell cycle progression impacts the tumor suppressor p53
Area of Science:
- Molecular Biology
- Cell Biology
- Genetics
Background:
- Cell fate decisions after genotoxic stress rely on p53 tumor suppressor activity.
- Precise p53 regulation is crucial for tissue homeostasis and cancer prevention.
- The influence of cell cycle progression on p53's cell fate decisions remains largely unelucidated.
Purpose of the Study:
- To investigate the impact of cell cycle progression on p53-mediated apoptosis.
- To explore the role of the G2/M kinase Cdk1 in regulating p53 activity.
- To understand how cell cycle status affects p53's proapoptotic function.
Main Methods:
- Utilized Drosophila melanogaster as a model organism.
- Experimentally induced cell cycle arrest and endoreplication.
- Assessed p53 binding to proapoptotic gene regulatory elements.
- Analyzed p53-Cdk1 interactions.
Main Results:
- Cell cycle-arrested and endoreduplicated cells exhibit refractoriness to ionizing radiation-induced apoptosis.
- p53's ability to bind and activate proapoptotic gene expression is impaired in arrested cells.
- p53 genetically and physically interacts with Cdk1.
- p53's proapoptotic function is modulated by the cell cycle status.
Conclusions:
- Cell cycle progression directly influences p53's proapoptotic activity.
- The G2/M kinase Cdk1 plays a role in regulating p53's response to DNA damage.
- A molecular connection exists between cell cycle progression and p53-mediated apoptosis.
- This connection is vital for coordinating cellular responses to DNA damage.
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