Role of compartmentalization on HiF-1? degradation dynamics during changing oxygen conditions: a computational approach.

ABSTRACT: HiF-1? is the central protein driving the cellular response to hypoxia. Its accumulation in cancer cells is linked to the appearance of chemoresistant and aggressive tumor phenotypes. As a consequence, understanding the regulation of HiF-1? dynamics is a major issue to design new anti-cancer therapies. In this paper, we propose a model of the hypoxia pathway, involving HiF-1? and its inhibitor pVHL. Based on data from the literature, we made the hypothesis that the regulation of HiF-1? involves two compartments (nucleus and cytoplasm) and a constitutive shuttle of the pVHL protein between them. We first show that this model captures correctly the main features of HiF-1? dynamics, including the bi-exponential degradation profile in normoxia, the kinetics of induction in hypoxia, and the switch-like accumulation. Second, we simulated the effects of a hypoxia/reoxygenation event, and show that it generates a strong instability of HiF-1?. The protein concentration rapidly increases 3 hours after the reoxygenation, and exhibits an oscillating pattern. This effect vanishes if we do not consider compartmentalization of HiF-1?. This result can explain various counter-intuitive observations about the specific molecular and cellular response to the reoxygenation process. Third, we simulated the HiF-1? dynamics in the tumor case. We considered different types of mutations associated with tumorigenesis, and we compared their consequences on HiF-1? dynamics. Then, we tested different therapeutics strategies. We show that a therapeutic decrease of HiF-1? nuclear level is not always correlated with an attenuation of reoxygenation-induced instabilities. Thus, it appears that the design of anti-HiF-1? therapies have to take into account these two aspects to maximize their efficiency.

SUBMITTER: Bedessem B 

PROVIDER: S-EPMC4206521 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature