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Open Access Highly Accessed Research article

Ligand-specific sequential regulation of transcription factors for differentiation of MCF-7 cells

Yuko Saeki15, Takaho Endo2, Kaori Ide1, Takeshi Nagashima15, Noriko Yumoto15, Tetsuro Toyoda2, Harukazu Suzuki3, Yoshihide Hayashizaki3, Yoshiyuki Sakaki4 and Mariko Okada-Hatakeyama15*

Author Affiliations

1 Cellular Systems Modeling Team, Computational Systems Biology Research Group, Advanced Computational Sciences Department, RIKEN Advanced Science Institute, 1-7-22 Suehiro-cho Tsurumi-ku Yokohama, Kanagawa, 230-0045 Japan

2 Bioinformatics and Systems Engineering Division, RIKEN Yokohama Institute, 1-7-22 Suehiro-cho Tsurumi-ku Yokohama, Kanagawa, 230-0045 Japan

3 RIKEN Omics Science Center, RIKEN Yokohama Institute, 1-7-22 Suehiro-cho Tsurumi-ku Yokohama, Kanagawa, 230-0045 Japan

4 Toyohashi University of Technology, 1-1 Hibarigaoka, Tempaku-cho, Toyohashi, Aichi, 441-8580, Japan

5 Cellular Systems Modeling Team, Research Center for Allergy and Immunology, RIKEN Yokohama Institute, 1-7-22 Suehiro-cho Tsurumi-ku Yokohama, Kanagawa, 230-0045 Japan

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BMC Genomics 2009, 10:545  doi:10.1186/1471-2164-10-545

Published: 20 November 2009

Abstract

Background

Sharing a common ErbB/HER receptor signaling pathway, heregulin (HRG) induces differentiation of MCF-7 human breast cancer cells while epidermal growth factor (EGF) elicits proliferation. Although cell fates resulting from action of the aforementioned ligands completely different, the respective gene expression profiles in early transcription are qualitatively similar, suggesting that gene expression during late transcription, but not early transcription, may reflect ligand specificity. In this study, based on both the data from time-course quantitative real-time PCR on over 2,000 human transcription factors and microarray of all human genes, we identified a series of transcription factors which may control HRG-specific late transcription in MCF-7 cells.

Results

We predicted that four transcription factors including EGR4, FRA-1, FHL2, and DIPA should have responsibility of regulation in MCF-7 cell differentiation. Validation analysis suggested that one member of the activator protein 1 (AP-1) family, FOSL-1 (FRA-1 gene), appeared immediately following c-FOS expression, might be responsible for expression of transcription factor FHL2 through activation of the AP-1 complex. Furthermore, RNAi gene silencing of FOSL-1 and FHL2 resulted in increase of extracellular signal-regulated kinase (ERK) phosphorylation of which duration was sustained by HRG stimulation.

Conclusion

Our analysis indicated that a time-dependent transcriptional regulatory network including c-FOS, FRA-1, and FHL2 is vital in controlling the ERK signaling pathway through a negative feedback loop for MCF-7 cell differentiation.