Mathematical modelling of the canonical NF-κB pathway

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The regulation of the transcription factor NF-kappaB is vital for physiological processes, affecting cell differentiation, proliferation, and survival. Experiments have shown significant variability in NF-kappaB dynamics, including sustained oscillations, damped oscillations, and monotonic increases leading to stable states. This work employs a theoretical approach to explore the internal sources of this variability. A core model of the canonical NF-kappaB pathway was developed, utilizing bifurcation analysis to investigate its dynamical properties. Key parameters influencing NF-kappaB dynamics include total NF-kappaB concentration and the transcription rate constant of the inhibitor IkappaBalphaw. The activation and deactivation of NF-kappaB are regulated by negative feedback loops, with the transcription of inhibitors IkappaBalpha and A20 induced by NF-kappaB itself. A mathematical model was created to incorporate these feedbacks and assess the impact of post-transcriptional regulation of the inhibitor mRNAs by the RNA-binding protein RC3H1 on NF-kappaB signal transduction. The analysis also examined the interplay between the feedbacks and cell type-specific differences, revealing that total NF-kappaB concentration significantly affects RC3H1's influence on NF-kappaB activity and the feedback interactions.