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

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

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  • 1Cellular Systems Biology Team, Computational and Experimental Systems Biology Group, RIKEN Genomic Sciences Center, 1-7-22 Suehiro-cho, Yokohama, Kanagawa 230-0045, Japan.

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.

PMID:
17142811
[PubMed - indexed for MEDLINE]
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