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J. Biol. Chem., Vol. 282, Issue 6, 4045-4056, February 9, 2007

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Quantitative Transcriptional Control of ErbB Receptor Signaling Undergoes Graded to Biphasic Response for Cell Differentiation^*

Takeshi Nagashima¹, Hidetoshi Shimodaira¹, Kaori Ide, Takashi Nakakuki, Yukitaka Tani, Kaoru Takahashi, Noriko Yumoto, and Mariko Hatakeyama²

From the Cellular Systems Biology Team, Computational and Experimental Systems Biology Group, RIKEN Genomic Sciences Center, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045 and the Department of Mathematical and Computing Sciences, Tokyo Institute of Technology, Ookayama, Meguro-ku, Tokyo 152-8552, Japan

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.

Received for publication, September 7, 2006 , and in revised form, November 29, 2006.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Methods, Tables S1-S3, and Figs. S1 and S2.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed. Tel.: 81-45-503-9302; Fax: 81-45-503-9613; E-mail: marikoh{at}gsc.riken.jp.

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