Co-regulation of B-Myb expression by E2F1 and EGF receptor
Co-regulation of B-Myb expression by E2F1 and EGF receptor
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DOI：
10.1002/mc.20147
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发表时间：
2006-01-01
影响因子：
4.6
通讯作者：
Hung, MC
中科院分区：
文献类型：
--
作者：
Hanada, N;Lo, HW;Hung, MC
表皮生长因子受体（EGFR）是一种受体酪氨酸激酶，在人类癌症中经常过度表达，与肿瘤发生、肿瘤增殖和进展增加有关。在乳腺肿瘤中也发现了高水平的B-Myb，这是一种转录因子，其表达在晚期G1期被E2 F1/3激活，并且该水平在整个S期持续。最近的报道表明EGFR和B-Myb在原发性乳腺癌中的表达存在因果关系。然而，这种共表达的机制仍然没有调查。在这里，我们报告说，EGFR是重要的B-Myb的表达和潜在的机制涉及EGFR和E2 F1的协同作用。EGF刺激和EGFR的强制表达显著增加B-Myb基因活性，并且这种增加发生在G（1）期。在抑制PI-3 K和ERK（两种主要的EGFR下游通路）后，EGF诱导的B-Myb表达未被显著抑制。相反，我们观察到EGF诱导的细胞核EGFR与B-Myb启动子的体内结合，这种结合仅在G（1）/S期检测到，并被EGFR激酶抑制剂消除。由于EGFR缺乏DNA结合结构域，但具有反式激活活性，而E2 F1在G1/S期激活B-Myb表达，我们进一步推断，细胞核EGFR可能与E2 F1协同激活B-Myb。事实上，我们发现EGFR以EGIF依赖性方式与E2 F1共免疫沉淀，并且EGF激活E2 F1与B-Myb启动子的体内结合。一致地，与载体对照和EGFR或E2 F1单独表达相比，EGFR和E2 F1在EGFR缺失CHO细胞中的强制表达大大增强了B-Myb启动子活性。启动子突变研究表明，含EGF的B-Myb启动子的激活需要E2 F和EGFR靶位点。总之，我们的数据表明，EGFR信号通路的失调促进肿瘤细胞增殖部分通过EGFR与E2 F1的相互作用和随后的B-Myb基因表达的激活。(c)2005 Wiley-Liss，Inc.
Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that is frequently over-expressed in human cancers and is associated with tumorigenesis, and increased tumor proliferation and progression. Also found in breast tumors with high levels is B-Myb, a transcription factor whose expression is activated by E2F1/3 at the late G, phase and the level is sustained through the S phase. Recent reports suggest a casual correlation between EGFR and B-Myb expression in primary breast carcinomas. However, the mechanism for such co-expression remains un-investigated. Here, we report that EGFR is important for B-Myb expression and the underlying mechanism involves cooperated effects from EGFR and E2F1. EGF stimulation and forced expression of EGFR significantly increase B-Myb gene activity and such increase occurs in the G(1) phase. EGF-incluced B-Myb expression was not significantly suppressed following inhibition of PI-3K and ERK, two major EGFR downstream pathways. In contrast, we observed EGF-induced in vivo association of nuclear EGFR to the B-Myb promoter and the association is only detected at the G(1)/S phase and is abolished by EGFR kinase inhibitor. As EGFR lacks DNA-binding domain but contains transactivational activity and E2F1 activates B-Myb expression in the G1/S phase, we further reasoned that nuclear EGFR might cooperate with E2F1 leading to activation of B-Myb. Indeed, we found that EGFR co-immunoprecipitated with E2F1 in an EGIF-dependent manner and that EGF activated in vivo binding of E2F1 to the B-Myb promoter. Consistently, forced expression of both EGFR and E2F1 in EGFR-null CHO cells greatly enhanced B-Myb promoter activity, compared to the vector control and expression of EGFR or E2F1 alone. Promoter mutagenesis studies showed that EGF-incluced activation of B-Myb promoter required both E2F and EGFR target sites. In summary, our data suggest that deregulated EGFR signaling pathway facilitate tumor cell proliferation partly via EGFR interaction with E2F1 and subsequent activation of B-Myb gene expression. (c) 2005 Wiley-Liss, Inc.