A systematic approach to decipher crosstalk in the p53 signaling pathway using single cell dynamics

Area of Science:

• Molecular Biology
• Cellular Signaling
• Systems Biology

Background:

• Nuclear factor kappa B (NF-κB) and p53 are crucial transcription factors regulating cellular responses to genotoxic stress.
• These pathways are critical in tumor development, but the intricate crosstalk between them remains incompletely understood.

Purpose of the Study:

• To systematically identify and characterize potential interactions between NF-κB and p53 signaling networks.
• To quantitatively analyze the impact of NF-κB pathway perturbation on p53 dynamics under genotoxic stress.

Main Methods:

• Perturbation of NF-κB signaling via IKK2 inhibition.
• Single-cell time-lapse microscopy to monitor p53 response to genotoxic stress.
• Development and fitting of subpopulation-specific computational p53 models to time-resolved data.

Main Results:

• Quantitative reproduction of signaling dynamics and cellular heterogeneity under unperturbed and perturbed conditions.
• Identification of integrated effects of IKK/NF-κB perturbation on p53 dynamics.
• Demonstration that simultaneous perturbation of p53 activation, p53 degradation, and Mdm2 degradation is required to explain observed p53 response changes.

Conclusions:

• The study highlights significant crosstalk between NF-κB and p53 networks, impacting cellular functions.
• Understanding these integrated network effects is crucial for comprehending tumor development and potential therapeutic strategies.
• The developed systematic approach provides a quantitative framework for dissecting complex signaling pathway interactions.