Quantitative transcriptional control of ErbB receptor signaling undergoes graded to biphasic response for cell differentiation
Quantitative transcriptional control of ErbB receptor signaling undergoes graded to biphasic response for cell differentiation
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DOI：
10.1074/jbc.m608653200
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发表时间：
2007-02-09
影响因子：
4.8
通讯作者：
Hatakeyama, Mariko
中科院分区：
文献类型：
--
作者：
Nagashima, Takeshi;Shimodaira, Hidetoshi;Hatakeyama, Mariko
ErbB受体配体，表皮生长因子(EGF)和Hereglin(HRG)分别诱导MCF-7乳腺癌细胞的瞬时和持续的细胞内信号转导、增殖和分化，并具有剂量依赖性。为了阐明配体特异的细胞决定机制，我们研究了EGF和HRG诱导MCF-7细胞不同表型的时程基因表达。为了独立分析配基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到早期转录。结果还表明，一些基因表达水平的适度变化，而不是少数特定基因的主导调控，可能在转录的早期阶段协同作用，决定细胞的命运。然而，EGF和HRG诱导的不同信号持续时间导致了20min后面向配体的蛋白质双相诱导。选择的基因列表和HRG诱导的延长信号表明，细胞内信号的转录反馈导致了细胞决定过程中的分级到双相反应，每个ErbB受体都对细胞生化反应的幅度和持续时间起着不可或缺的作用。
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.