An intermediary role of proHB-EGF shedding in growth factor-induced c-Myc gene expression
An intermediary role of proHB-EGF shedding in growth factor-induced c-Myc gene expression
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DOI：
10.1002/jcp.21233
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发表时间：
2008-02-01
影响因子：
5.6
通讯作者：
Higashiyama, Shigeki
中科院分区：
文献类型：
--
作者：
Nanba, Daisuke;Inoue, Hirofumi;Higashiyama, Shigeki
通过配体结合激活生长因子受体导致c-Myc表达增加，c-Myc是细胞增殖的转录调节因子。通过激活受体激活转录因子被认为是c-Myc基因表达的主要作用。我们在这里证明了表皮生长因子受体(EGFR)和成纤维细胞生长因子受体(FGFR)在原代培养的小鼠胚胎成纤维细胞(MEF)中介导的c-Myc诱导和细胞周期进展可以通过敲除肝素结合的EGF-like生长因子(HB-EGF)基因或被金属蛋白酶抑制剂取消，尽管受体下游的分子被激活。在HB-EGF缺失的MEF中，野生型proHB-EGF过表达可恢复EGF或碱性成纤维细胞生长因子对c-Myc表达的诱导，而proHB-EGF的不可切割突变体未见恢复。这个不能切割的突变体还抑制了EGF诱导的小鼠c-Myc第一内含子区域组蛋白H3的乙酰化，这可能会对转录激活产生负面影响。我们认为，脱毛事件中由proHB-EGF的羧基末端片段(HB-EGF-CTF)启动的信号转导在生长因子受体激活和c-Myc基因诱导之间起着重要的中介作用。
Activation of growth factor receptors by ligand binding leads to an increased expression of c-Myc, a transcriptional regulator for cell proliferation. The activation of transcriptional factors via the activated receptors is thought to be the main role of c-Myc gene expression. We demonstrate here that epidermal growth factor receptor (EGFR)- and fibroblast growth factor receptor (FGFR)-mediated c-Myc induction and cell cycle progression in primary cultured mouse embryonic fibroblasts (MEFs) are abrogated by knockout of the heparin-binding EGF-like growth factor (Hb-egf) gene, or by a metalloproteinase inhibitor, although molecules downstream of the receptors are activated. Induction of c-Myc expression by EGF or basic FGF is recovered in Hb-egf-depleted MEFs by overexpression of wild-type proHB-EGF, but no recovery was observed with an uncleavable mutant of proHB-EGF. The uncleavable mutant also inhibited EGF-induced acetylation of histone H3 at the mouse c-Myc first intron region, which could negatively affect transcriptional activation. We conclude that signal transduction initiated by generation of the carboxyl-terminal fragment of proHB-EGF (HB-EGF-CTF) in the shedding event plays an important intermediary role between growth factor receptor activation and c-Myc gene induction.