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.
Highlights
The different kinetics displayed by extracellular signal-regulated kinase (ERK)3 activation often results in distinct cellular phenotypes of mammalian cells
This study on the ErbB receptor-mediated early transcription indicated that the quantitative feature of transcriptional regulation was determined by receptor activation kinetics
Previous gene expression studies using M-CSF-stimulated M-CSF-platelet-derived growth factor (PDGF) receptor chimeras showed that diverse signaling pathways resulted in broadly overlapping early gene expression [22], another experimental setup using similar PDGF receptor chimeras, which possess different ligand affinity and duration of ERK activity, showed divergent embryological functions in mice [51]
Summary
Our quantitative transcriptional analysis indicated that EGF and HRG induced overlapping early transcription, with a large difference in their expression levels. Our results showed that ligand-specific dose-dependent activation of signal transduction pathways is precisely transmitted to early transcription, which was initially graded, induced ligand-oriented biphasic induction of c-Fos proteins after 20 min. For this mechanism, the duration of intracellular signaling, which was prolonged by ErbB receptor and, possibly, early transcription products, seemed to be responsible for this event. Our analysis indicated that MCF-7 cells utilize dosedependent graded responses and transcriptional feedback to maintain signal duration to induce a biphasic response for cell determination and that expression of the ErbB receptor species is the most critical parameter to control the quantitative aspects of cellular processes
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