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HIF (Hypoxia Inducible Factor) is an oxygen-regulated transcription factorthat mediates the intracellular response to hypoxia in human cells. There isincreasing evidence that cell signaling pathways encode temporal information,and thus cell fate may be determined by the dynamics of protein levels. We havedeveloped a mathematical model to describe the transient dynamics of theHIF-1{\alpha} protein measured in single cells subjected to hypoxic shock. Theessential characteristics of these data are modeled with a system ofdifferential equations describing the feedback inhibition between HIF-1{\alpha}and Prolyl Hydroxylases (PHD) oxygen sensors. Heterogeneity in the single-celldata is accounted for through parameter variation in the model. We previouslyidentified the PHD2 isoform as the main PHD responsible for controlling theHIF-1{\alpha} transient response, and make here testable predictions regardingHIF-1{\alpha} dynamics subject to repetitive hypoxic pulses. The model isfurther developed to describe the dynamics of HIF-1{\alpha} in cells culturedas 3D spheroids, with oxygen dynamics parameterized using experimentalmeasurements of oxygen within spheroids. We show that the dynamics ofHIF-1{\alpha} and transcriptional targets of HIF-1{\alpha} display anon-monotone response to the oxygen dynamics. Specifically we demonstrate thatthe dynamic transient behavior of HIF-1{\alpha} results in differentialdynamics in transcriptional targets.

Modeling the dynamics of hypoxia inducible factor-1{\alpha} (HIF-1{\alpha}) within single cells and 3D cell culture systems