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

摘要

HIP (hypoxia inducible factor) is an oxygen-regulated transcription factor that mediates the intracellular response to hypoxia in human cells. There is increasing evidence that cell signaling pathways encode temporal information, and thus cell fate may be determined by the dynamics of protein levels. We have developed a mathematical model to describe the transient dynamics of the HIF-1 alpha protein measured in single cells subjected to hypoxic shock. The essential characteristics of these data are modeled with a system of differential equations describing the feedback inhibition between HIP-1 alpha and prolyl hydroxylases (PHD) oxygen sensors. Heterogeneity in the single-cell data is accounted through parameter variation in the model. We previously identified the PHD2 isoform as the main PHD sensor responsible for controlling the HIP-1 alpha transient response, and make here testable predictions regarding HIF-1 alpha dynamics subject to repetitive hypoxic pulses. The model is further developed to describe the dynamics of HIP-1 alpha in cells cultured as 3D spheroids, with oxygen dynamics parameterized using experimental measurements of oxygen within spheroids. We show that the dynamics of HIP-1 alpha and transcriptional targets of HIP-1 alpha display a non-monotone response to the oxygen dynamics. Specifically we demonstrate that the dynamic transient behavior of HIP-1 alpha results in differential dynamics in transcriptional targets. (C) 2014 Elsevier Inc. All rights reserved.