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

Yuko Saeki, Takaho Endo, Kaori Ide, Takeshi Nagashima, Noriko Yumoto, Tetsuro Toyoda, Harukazu Suzuki, Yoshihide Hayashizaki, Yoshiyuki Sakaki, Mariko Okada-Hatakeyama

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29 Citations (Scopus)

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.

Original languageEnglish
Article number545
JournalBMC Genomics
Volume10
DOIs
Publication statusPublished - 2009 Nov 20

ASJC Scopus subject areas

  • Biotechnology
  • Genetics

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    Saeki, Y., Endo, T., Ide, K., Nagashima, T., Yumoto, N., Toyoda, T., Suzuki, H., Hayashizaki, Y., Sakaki, Y., & Okada-Hatakeyama, M. (2009). Ligand-specific sequential regulation of transcription factors for differentiation of MCF-7 cells. BMC Genomics, 10, [545]. https://doi.org/10.1186/1471-2164-10-545