Nagashima Takeshi, Shimodaira Hidetoshi, Ide Kaori, Nakakuki Takashi, Tani Yukitaka, Takahashi Kaoru, Yumoto Noriko, Hatakeyama Mariko
Cellular Systems Biology Team, Computational and Experimental Systems Biology Group, RIKEN Genomic Sciences Center, 1-7-22 Suehiro-cho, Yokohama, Kanagawa 230-0045, Japan.
J Biol Chem. 2007 Feb 9;282(6):4045-56. doi: 10.1074/jbc.M608653200. Epub 2006 Dec 1.
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.
表皮生长因子（EGF）和神经调节蛋白（HRG）这两种ErbB受体配体，分别诱导MCF-7乳腺癌细胞产生剂量依赖性的瞬时和持续细胞内信号传导、增殖及分化。为了阐明配体特异性的细胞决定机制，我们研究了由EGF和HRG诱导的、在MCF-7细胞中产生不同细胞表型的时间进程基因表达。为了独立分析配体剂量和时间对基因表达的影响，我们开发了一种统计方法来估计这两种影响。我们的结果表明，信号转导通路将ErbB受体剂量依赖性激活的定量特性传递至早期转录过程。结果还表明，许多基因表达水平的适度变化，而非少数特定基因的主导调控，可能在转录早期协同作用以决定细胞命运。然而，EGF和HRG诱导的不同信号持续时间导致在20分钟后出现配体导向的蛋白质双相诱导。所选基因列表以及HRG诱导的延长信号表明，对细胞内信号传导的转录反馈在细胞决定过程中导致从分级到双相的反应，并且每个ErbB受体对细胞生化反应的幅度和持续时间的控制都有着密不可分的作用。
