An internal ribosome entry site in the 5' untranslated region of epidermal growth factor receptor allows hypoxic expression.
An internal ribosome entry site in the 5' untranslated region of epidermal growth factor receptor allows hypoxic expression.
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DOI：
10.1038/oncsis.2014.43
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发表时间：
2015-01-26
期刊：
影响因子：
6.2
通讯作者：
Spriggs, K. A.
中科院分区：
文献类型：
--
作者：
Webb, T. E.;Hughes, A.;Smalley, D. S.;Spriggs, K. A.
表皮生长因子受体（EGFR/ERBB 1/HER 1）的表达与许多癌症的进展有关，这一特征已被用于开发EGFR抗体和EGFR酪氨酸激酶抑制剂作为抗癌药物。然而，EGFR也具有重要的正常细胞功能，当EGFR被抑制时会导致严重的副作用。许多癌基因的一个破坏性特征是在与肿瘤内部相关的缺氧条件下表达的能力。先前已经证明，EGFR的表达通过未知的翻译控制机制在缺氧条件下得以维持，尽管总体翻译速率在缺氧条件下通常减弱。在本报告中，我们证明了人EGFR 5′非翻译区（UTR）序列可以通过内部核糖体进入位点（IRES）启动下游开放阅读框架的表达。我们表明，这种效果是不是由于无论是神秘的启动子活性或剪接事件。我们研究了EGFR IRES对真核起始因子4A（eIF 4A）的需求，eIF 4A是一种RNA解旋酶，负责处理RNA二级结构，作为翻译起始的一部分。用马嘌呤醇（一种有效的eIF 4A抑制剂）治疗导致EGFR 5′ UTR驱动的报告基因活性降低，EGFR蛋白水平也降低。重要的是，我们表明，表达的报告基因的EGFR IRES的控制下，保持在缺氧条件下，尽管在全球翻译率下降。
The expression of epidermal growth factor receptor (EGFR/ERBB1/HER1) is implicated in the progress of numerous cancers, a feature that has been exploited in the development of EGFR antibodies and EGFR tyrosine kinase inhibitors as anti-cancer drugs. However, EGFR also has important normal cellular functions, leading to serious side effects when EGFR is inhibited. One damaging characteristic of many oncogenes is the ability to be expressed in the hypoxic conditions associated with the tumour interior. It has previously been demonstrated that expression of EGFR is maintained in hypoxic conditions via an unknown mechanism of translational control, despite global translation rates generally being attenuated under hypoxic conditions. In this report, we demonstrate that the human EGFR 5′ untranslated region (UTR) sequence can initiate the expression of a downstream open reading frame via an internal ribosome entry site (IRES). We show that this effect is not due to either cryptic promoter activity or splicing events. We have investigated the requirement of the EGFR IRES for eukaryotic initiation factor 4A (eIF4A), which is an RNA helicase responsible for processing RNA secondary structure as part of translation initiation. Treatment with hippuristanol (a potent inhibitor of eIF4A) caused a decrease in EGFR 5′ UTR-driven reporter activity and also a reduction in EGFR protein level. Importantly, we show that expression of a reporter gene under the control of the EGFR IRES is maintained under hypoxic conditions despite a fall in global translation rates.
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