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

Takeshi Nagashima, Hidetoshi Shimodaira, Kaori Ide, Takashi Nakakuki, Yukitaka Tani, Kaoru Takahashi, Noriko Yumoto, Mariko Hatakeyama

Research output: Contribution to journalArticlepeer-review

113 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)4045-4056
Number of pages12
JournalJournal of Biological Chemistry
Volume282
Issue number6
DOIs
Publication statusPublished - 2007 Jan 9

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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