DESCRIPTION AND ANALYSIS OF SWITCHLIKE REGULATORY NETWORKS EXEMPLIFIED BY A MODEL OF CELLULAR IRON HOMEOSTASIS

The post-transcriptional regulation of factors involved in the mainten ance of cellular iron homeostasis is exerted by iron regulatory protei ns (IRPs), which bind to mRNA structures known as iron regulatory elem ents (IREs). The IRP-IRE interactions are regulated by the intracellul ar iron level by affecting the binding affinity, synthesis and stabili ty of the IRPs. A model of this homeostasis phenomenon is described an d analysed within a methodological framework specifically designed for handling complex systems with steep sigmoidal input/output relationsh ips between the state variables. According to the analysis there is on ly one threshold regulated homeostatic point. Approximate values for i ts coordinates, and the conditions ensuring its existence, may be give n in terms of the parameters. The analysis also provides some tentativ e insight into the evolution of the regulatory system. A comparison be tween analytical and numerical estimates of the position of the statio nary point as a function of the steepness of the sigmoidal interaction s shows that the analytical approximations agree quite well with the n umerical ones. The results show that we are able to obtain a deeper an alytical insight by this methodological framework than what is achieva ble by most alternative approaches. We find this type of insight to be of considerable heuristic value in connection with the numerical simu lation work which normally must be done to unfold the predictive poten tial of a complex model. (C) 1998 Academic Press.