title: 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.
authors.affiliation: Cellular Systems Biology Team, Computational and Experimental Systems Biology Group, RIKEN Genomic Sciences Center, 1-7-22 Suehiro-cho, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nagashima
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Shimodaira
authors.forename: Kaori
authors.initials: K
authors.lastname: Ide
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakakuki
authors.forename: Yukitaka
authors.initials: Y
authors.lastname: Tani
authors.forename: Kaoru
authors.initials: K
authors.lastname: Takahashi
authors.forename: Noriko
authors.initials: N
authors.lastname: Yumoto
authors.forename: Mariko
authors.initials: M
authors.lastname: Hatakeyama
mesh_terms: D002454:Cell Differentiation / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004815:Epidermal Growth Factor / Q000378:metabolism / Q000502:physiology; D025461:Feedback, Physiological; D006801:Humans; D007700:Kinetics; D008024:Ligands; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D020890:Neuregulin-1 / Q000378:metabolism / Q000502:physiology; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism / Q000502:physiology*; D015290:Second Messenger Systems / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics*; D014158:Transcription, Genetic
chemical_list: D004815:Epidermal Growth Factor; D008024:Ligands; D048052:Mitogen-Activated Protein Kinase 3; D020890:Neuregulin-1; D051057:Proto-Oncogene Proteins c-akt; D016760:Proto-Oncogene Proteins c-fos; D018719:Erb-b2 Receptor Tyrosine Kinases