ErbB380 kDa, a nuclear variant of the ErbB3 receptor, binds to the Cyclin D1 promoter to activate cell proliferation but is negatively controlled by p14ARF
ErbB380 kDa, a nuclear variant of the ErbB3 receptor, binds to the Cyclin D1 promoter to activate cell proliferation but is negatively controlled by p14ARF
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DOI：
10.1016/j.cellsig.2012.01.002
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发表时间：
2012-05-01
影响因子：
4.8
通讯作者：
Seite, Paule
中科院分区：
文献类型：
--
作者：
Andrique, Laetitia;Fauvin, Dominique;Seite, Paule
EGFR家族成员是酪氨酸激酶跨膜受体，其响应于特异性细胞外配体，激活参与细胞增殖、迁移和分化的细胞质途径。最近，通过描述其核定位，EGF受体的关键作用已经出现。我们在这里报告的激酶缺陷型ErbB3受体，ErbB3（80）（kDa），跨越胞浆内域的受体的核变体的表征。我们评估了ErbB3（80）（kDa）在癌细胞中的假定转录功能，通过调节增殖细胞周期蛋白D1基因，ErbB3细胞质信号传导的已知靶点。我们在这里证明，ErbB3（80）（kDa）的启动子上的结合激活细胞周期蛋白D1的转录和随后的蛋白质表达，导致细胞增殖增加。这一机制可以在肿瘤抑制因子p14（ARF）的异位表达中得到平衡，ARF与ErbB3（100）（kDa）发生物理相互作用并将其隔离到核仁中。我们的数据还表明，ErbB3（80）（kDa）增加了增殖基因的转录，即使细胞质途径没有被激活。ErbB3核内通路及其靶基因有待进一步研究。事实上，这种机制可以解释在响应于旨在阻断响应于配体结合的受体活化的治疗中观察到的肿瘤复发。(C)2012 Elsevier Inc. All rights reserved.
EGFR family members are tyrosine kinase transmembrane receptors that, in response to specific extracellular ligands, activate cytoplasmic pathways involved in cell proliferation, migration and differentiation. More recently, a pivotal role for EGF receptors has emerged, through the description of their nuclear localization. We report here the characterization of a nuclear variant of the kinase-defective ErbB3 receptor, ErbB3(80) (kDa), spanning the intracytoplasmic domain of the receptor. We assessed the putative transcriptional functions of ErbB3(80) (kDa) in cancer cells, through the regulation of the proliferative Cyclin D1 gene, an already known target of the ErbB3 cytoplasmic signaling. We demonstrate here that the binding of ErbB3(80) (kDa) on the promoter activates Cyclin D1 transcription and subsequent protein expression, leading to an increased cell proliferation. This mechanism can be balanced in response to the ectopic expression of the tumor suppressor p14(ARF) that physically interacts with ErbB3(100) (kDa) and sequesters it into nucleoli.Our data also show that ErbB3(80) (kDa) increases the transcription of proliferative genes even though the cytoplasmic pathways are not activated. This nuclear ErbB3 pathway and the target genes concerned need to be further studied. Indeed, such mechanism could explain the tumor relapse observed in response to treatments aimed at blocking the receptor activation in response to ligand binding. (C) 2012 Elsevier Inc. All rights reserved.