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


CONCLUSIONS
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.
Saeki
Yuko
Y
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.
Endo
Takaho
T
Ide
Kaori
K
Nagashima
Takeshi
T
Yumoto
Noriko
N
Toyoda
Tetsuro
T
Suzuki
Harukazu
H
Hayashizaki
Yoshihide
Y
Sakaki
Yoshiyuki
Y
Okada-Hatakeyama
Mariko
M
D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor; D004815:Epidermal Growth Factor / Q000494:pharmacology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D008024:Ligands; D020890:Neuregulin-1 / Q000494:pharmacology; D010641:Phenotype; D016133:Polymerase Chain Reaction; D034622:RNA Interference; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism
D008024:Ligands; D020890:Neuregulin-1; D014157:Transcription Factors; D004815:Epidermal Growth Factor