Epidermal growth factor receptor stimulation activates the RNA bindin protein CUG-BP1 and increases expression of C/EBPβ-LIP in mammary epithelial cells
Epidermal growth factor receptor stimulation activates the RNA bindin protein CUG-BP1 and increases expression of C/EBPβ-LIP in mammary epithelial cells
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DOI：
10.1128/mcb.24.9.3682-3691.2004
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发表时间：
2004-05-01
影响因子：
5.3
通讯作者：
Zahnow, CA
中科院分区：
文献类型：
--
作者：
Baldwin, BR;Timchenko, NA;Zahnow, CA
转录因子CCAAT/增强子结合蛋白β (C/EBPbeta)是许多组织生长和分化的关键调节因子。C/ ebp β以几种不同的蛋白异构体（LAP1、LAP2和LIP）表达，其表达受下游AUG起始位点的替代翻译起始调控。显性阴性LIP亚型主要在增殖细胞反应中表达，并与侵袭性肿瘤有关。在这项研究中，我们研究了LIP异构体在乳腺上皮细胞中被翻译调节的机制。我们已经证明，在表皮生长因子受体（EGFR）信号通路激活的情况下，LIP的表达增加，并且LIP的表达增加部分受到一种称为CUG重复结合蛋白（CUG- bp1）的RNA结合蛋白的调节。我们的数据表明，EGFR信号导致CUG-BP1磷酸化，从而导致CUG-BP1与C/EBPbeta mRNA结合增加，LIP亚型表达升高。磷酸化对于ug - bp1的结合活性和随之而来的LIP表达的增加是必要的，这是通过结合实验和无细胞的转录偶联翻译系统确定的。因此，ug - bp1是之前未被发现的EGFR信号传导的下游靶点，代表了人乳腺上皮细胞中LIP表达的一种新的翻译调节因子。
The transcription factor CCAAT/enhancer binding protein beta (C/EBPbeta) is a key regulator of growth and differentiation in many tissues. C/EBPbeta is expressed as several distinct protein isoforms (LAP1, LAP2, and LIP) whose expression is regulated by alternative translational initiation at downstream AUG start sites. The dominant-negative LIP isoform is predominantly expressed during proliferative cellular responses and is associated with aggressive tumors. In this study, we investigated a mechanism by which the LIP isoform is translationally regulated in mammary epithelial cells. We have demonstrated that LIP expression is increased in response to activation of the epidermal growth factor receptor (EGFR) signaling pathway and that the increased expression of LIP is regulated in part by an RNA binding protein referred to as CUG repeat binding protein (CUG-BP1). Our data demonstrate that EGFR signaling results in the phosphorylation of CUG-BP1 and this leads to an increase in the binding of CUG-BP1 to C/EBPbeta mRNA and elevated expression of the LIP isoform. Phosphorylation is necessary for the binding activity of CUG-BP1 and the consequent increase in LIP expression, as determined by binding assays and a cell free, transcription-coupled translation system. CUG-BP1 is thus a previously unidentified downstream target of EGFR signaling and represents a new translational regulator of LIP expression in human mammary epithelial cells.