A mathematical approach for the transactivation of hERalpha

Several reports over the last few years have documented the dose-response curve for steroid hormone induction of gene transcription as a modulated property of a given receptor-agonist complex that varies with the changing concentration of a variety of factors including: homologous receptor, co-activators, co-repressors and selected co-factors. In each report, the dose-response curves are sigmoidal and show an excellent fit with the curve generated by Michaelis-Menten kinetics. In addition, even the overall function of human oestrogen receptors (hERs) can show a similar graph for the determination of sex versus oestrogen compounds in reptiles. Thus, the kinetic properties of the simple bimolecular reaction of A+B-->C appear, surprisingly, to be sufficient to describe the dose-response curve of the multi-step process of steroid-regulated gene induction that involves several molecules. Any advance in explaining why the dose-response curve for steroid-regulated gene expression is sigmoidal would assist in understanding what parameters are key factors of the dose-response curve and can benefit in the design of new oestrogenic substances. We have constructed and analysed a multi-step model of hER-induced gene transcription that explains the multiple forms of a simple dose-response curve in an in vitro transcription system.