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Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
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p53 dynamics orchestrates with binding affinity to target genes for cell fate decision
Mengqiu Wu1,2, Hui Ye1, Zhiyuan Tang3
1Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Tongjiaxiang #24, Nanjing, Jiangsu 210009, China.
Cell Death & Disease
|October 20, 2017
Summary
p53 protein dynamics and gene binding affinity together control cell fate decisions. Effective cumulative p53 levels above a threshold, not total accumulation, determine apoptosis or survival, guiding cancer drug strategies.
Area of Science:
- Molecular Biology
- Cell Biology
- Biophysics
Background:
- Temporal dynamics of signaling molecules are crucial for cellular responses.
- The tumor suppressor p53 protein uses dynamic signaling for selective gene activation and cell fate determination.
- Quantitative understanding of p53 dynamics in cell fate decisions remains incomplete.
Purpose of the Study:
- To elucidate the quantitative mechanism by which p53 dynamics and binding affinity orchestrate cell fate decisions.
- To investigate how p53 protein levels and temporal patterns influence the transactivation of target genes.
- To establish a framework for understanding p53's quantitative response to chemotherapeutic agents.
Main Methods:
- Treatment of cells with varying doses and durations of the genotoxic drug doxorubicin.
- Quantitative analysis of p53 protein pulses and accumulation levels.
- Assessment of p53 binding affinity to proapoptotic and proarrest genes.
- Correlation of p53 dynamics and binding affinity with cell survival and apoptosis outcomes.
Main Results:
- Mild, prolonged doxorubicin treatment induced sequential p53 pulses, leading to apoptosis comparable to acute high-dose treatment.
- Effective cumulative p53 levels above a threshold (E∫p53), not total accumulation, accurately predicted cell fate.
- p53 failed to transactivate low-affinity proapoptotic genes when accumulation remained below the threshold, irrespective of duration.
- p53 dynamics and gene binding affinity synergistically determine cell fate, with affinity being critical for low-affinity targets.
Conclusions:
- Cell fate is determined by the interplay between p53 protein dynamics and its binding affinity to target genes.
- A quantitative threshold and sufficient duration of p53 accumulation are necessary for transactivating proapoptotic genes.
- The findings provide insights into p53's quantitative response to chemotherapy and inform the design of metronomic drug regimens.
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