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

J Biol Chem. 2007 Feb 9;282(6):4045-56. doi: 10.1074/jbc.M608653200. Epub 2006 Dec 1.

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.

MeSH terms

  • Cell Differentiation / genetics*
  • Cell Line, Tumor
  • Cell Proliferation
  • Epidermal Growth Factor / metabolism
  • Epidermal Growth Factor / physiology
  • Feedback, Physiological
  • Humans
  • Kinetics
  • Ligands
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Neuregulin-1 / metabolism
  • Neuregulin-1 / physiology
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / metabolism
  • Proto-Oncogene Proteins c-fos / biosynthesis
  • Proto-Oncogene Proteins c-fos / genetics
  • Receptor, ErbB-2 / metabolism
  • Receptor, ErbB-2 / physiology*
  • Second Messenger Systems / genetics
  • Signal Transduction / genetics*
  • Transcription, Genetic*

Substances

  • Ligands
  • Neuregulin-1
  • Proto-Oncogene Proteins c-fos
  • Epidermal Growth Factor
  • Receptor, ErbB-2
  • Proto-Oncogene Proteins c-akt
  • Mitogen-Activated Protein Kinase 3