Characterisation of cellular factors that modulate VEGF IRES-dependent translation initiation

血管内皮生长因子A(VEGF)是生理性和病理性血管生成的重要调节因子之一。血管内皮生长因子的表达在转录水平受到严格调控，但对其转录后调控知之甚少。血管内皮生长因子基因5‘端非编码区包含两个独立的内部核糖体进入位点A和B，它们能够以5’端非依赖帽的方式促进有效的翻译。该项目将集中于确定和功能分析所需的细胞因子，以血管内皮生长因子IRES驱动的翻译以及乳腺癌细胞中的血管内皮生长因子3‘非编码区在这一过程中的功能。我们将研究在这些复合体中具有功能相关性的单个因子的复杂组成和/或翻译后修饰(S)。体外和体内实验的结果将有助于阐明翻译以血管内皮生长因子IRES和3‘非编码区依赖的方式控制的机制。新特征的因子可能代表潜在的治疗靶点，可以进一步分析以确定干扰其在病理性血管生成中表达血管内皮生长因子的功能的化合物。

The vascular endothelial growth factor A (VEGF) is one of the most important regulators of both physiological and pathological angiogenesis. Expression of VEGF is tightly regulated at the transcriptional level, but little is known about its post-transcriptional control. The VEGF mRNA 5’UTR contains two independent internal ribosome entry sites (IRES) A and B, which are able to promote efficient translation in a 5’cap-independent manner. The project will focus on the identification and functional analysis of cellular factors that are required for VEGF IRES-driven initiation of translation as well as the function of the VEGF mRNA 3’UTR in this process in breast cancer cells. We will study the complex composition and/or post-translational modification(s) of individual factors that are of functional relevance in these complexes. The results of the in vitro and in vivo experiments will allow the elucidation of the mechanism by which translation is controlled in a VEGF IRES and 3’UTR-dependent manner. Newly characterised factors might represent potential therapeutic targets, which can be further analysed to identify compounds, which interfere with their function for VEGF expression in pathological angiogenesis.