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.
BMC Genomics. 2009 Nov 20;10:545. doi: 10.1186/1471-2164-10-545.
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.
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.
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.
作为一种共同的 ErbB/HER 受体信号通路，人表皮生长因子（heregulin，HRG）诱导 MCF-7 人乳腺癌细胞分化，而表皮生长因子（EGF）则引发增殖。尽管上述配体作用的细胞命运完全不同，但早期转录中的各自基因表达谱在质量上是相似的，这表明基因表达在晚期转录而不是早期转录中可能反映出配体的特异性。在这项研究中，基于对超过 2000 个人类转录因子的时间过程定量实时 PCR 数据和所有人类基因的微阵列，我们确定了一系列转录因子，这些转录因子可能控制 MCF-7 细胞中 HRG 特异性的晚期转录。
我们预测，包括 EGR4、FRA-1、FHL2 和 DIPA 在内的四个转录因子可能对 MCF-7 细胞分化的调控负责。验证分析表明，AP-1 家族的一个成员 FOSL-1（FRA-1 基因）在 c-FOS 表达后立即出现，可能通过激活 AP-1 复合物负责转录因子 FHL2 的表达。此外，FOSL-1 和 FHL2 的 RNAi 基因沉默导致细胞外信号调节激酶（ERK）磷酸化增加，而 HRG 刺激持续维持 ERK 磷酸化。
我们的分析表明，包括 c-FOS、FRA-1 和 FHL2 在内的一个时程转录调控网络对于 MCF-7 细胞分化通过负反馈回路控制 ERK 信号通路至关重要。
