Quantitative transcriptional control of ErbB receptor signaling undergoes graded to biphasic response for cell differentiation

Abstract

ErbB receptor ligands, epidermal growth factor (EGF) and heregulin (HRG), induce dose-dependent transient and sustained intracellular signaling, proliferation, and differentiation of MCF-7 breast cancer cells, respectively. In an effort to delineate the ligand-specific cell determination mechanism, we investigated time course gene expressions induced by EGF and HRG that induce distinct cellular phenotypes in MCF-7 cells. To analyze independently the effects of ligand dosage and time for gene expression, we developed a statistical method for estimating the two effects. Our results indicated that signal transduction pathways convey quantitative properties of the dose-dependent activation of ErbB receptor to early transcription. The results also implied that moderate changes in the expression levels of a number of genes, not the predominant regulation of a few specific genes, might cooperatively work at the early stage of the transcription for determining cell fate. However, the EGF- and HRG-induced distinct signal durations resulted in the ligand-oriented biphasic induction of proteins after 20 min. The selected gene list and HRG-induced prolonged signaling suggested that transcriptional feedback to the intracellular signaling results in a graded to biphasic response in the cell determination process and that each ErbB receptor is inextricably responsible for the control of amplitude and duration of cellular biochemical reactions.