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Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
Dying to Survive-The p53 Paradox
Andrea Lees1, Tamas Sessler1, Simon McDade1
1Patrick G Johnston Centre for Cancer Research, Queen's University, Belfast BT9 7AE, UK.
Abstract:
The p53 tumour suppressor is best known for its canonical role as "guardian of the genome", activating cell cycle arrest and DNA repair in response to DNA damage which, if irreparable or sustained, triggers activation of cell death. However, despite an enormous amount of work identifying the breadth of the gene regulatory networks activated directly and indirectly in response to p53 activation, how p53 activation results in different cell fates in response to different stress signals in homeostasis and in response to p53 activating anti-cancer treatments remains relatively poorly understood. This is likely due to the complex interaction between cell death mechanisms in which p53 has been activated, their neighbouring stressed or unstressed cells and the local stromal and immune microenvironment in which they reside. In this review, we evaluate our understanding of the burgeoning number of cell death pathways affected by p53 activation and how these may paradoxically suppress cell death to ensure tissue integrity and organismal survival. We also discuss how these functions may be advantageous to tumours that maintain wild-type p53, the understanding of which may provide novel opportunity to enhance treatment efficacy.
Insights
The p53 tumor suppressor, known as "guardian of the genome", can paradoxically suppress cell death to maintain tissue integrity. Understanding this role offers new strategies for enhancing anti-cancer treatment efficacy.
Area of Science:
- Molecular Biology
- Cell Biology
- Cancer Research
Background:
- The p53 protein acts as a tumor suppressor, often called the "guardian of the genome". It responds to DNA damage by halting the cell cycle or initiating cell death.
- While p53's role in DNA repair and cell death is established, how it dictates different cell fates under various stress conditions and during anti-cancer treatments is not fully understood.
Purpose of the Study:
- To review the diverse cell death pathways influenced by p53 activation.
- To explore how p53 may paradoxically suppress cell death to preserve tissue integrity.
- To discuss the implications for tumors with wild-type p53 and potential therapeutic strategies.
Main Methods:
- Literature review and synthesis of existing research on p53 function and cell death.
- Analysis of the interplay between p53, cellular microenvironments, and immune responses.
- Evaluation of p53's role in tissue homeostasis versus anti-cancer treatment contexts.
Main Results:
- p53 activation influences a growing number of cell death pathways.
- p53 can suppress cell death to maintain tissue integrity, a function that can be co-opted by tumors.
- The tumor microenvironment significantly impacts p53-mediated cell fate decisions.
Conclusions:
- Understanding the multifaceted roles of p53 in cell death regulation is crucial.
- p53's paradoxical suppression of cell death presents therapeutic opportunities for cancer treatment.
- Targeting p53-mediated pathways could enhance the efficacy of existing anti-cancer therapies.
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