Translational control of GATA-3

描述(申请人提供)：CD4+T细胞向Th2亚群的分化依赖于转录因子GATA-3，GATA-3通过多种机制促进Th2分化。GATA-3的表达和功能能力都是严格调控的过程，功能GATA-3蛋白水平的微小变化可以对细胞分化产生重大影响。我们最近发现，TCR信号通过选择性上调GATA-3的翻译率，在诱导GATA-3表达和随后的Th2分化过程中发挥关键作用。GATA-3的这种翻译上调依赖于通过PI3K/mTOR途径的TCR信号，我们的初步数据表明，这是通过5‘UTR中的RNA二级结构介导的。这些观察表明了一种翻译调控模型，其中TCR信号增强了eIF2A解旋酶的活性，这是核糖体扫描具有稳定二级结构的5‘UTR所必需的。这项建议的总体目标是定位GATA-3 5‘非编码区中的顺式元件，并确定调节GATA-3翻译速率的下游信号通路。这些研究的总体目标将是确定GATA-3中影响Th2效应细胞生成和稳定性的特定分子靶点，并可开发成控制包括哮喘在内的特应性疾病的实验方法。

DESCRIPTION (provided by applicant): The differentiation of CD4+ T cells into the Th2 subset is dependent on the transcription factor GATA-3, which promotes Th2 differentiation through multiple mechanisms. Both the expression and functional capacity of GATA-3 are tightly regulated processes and small changes in the level of functional GATA-3 protein can have significant effects on cellular differentiation. We have recently discovered that TCR signaling plays a critical role in the induction of GATA-3 expression and subsequent Th2 differentiation through the selective upregulation of GATA-3 translation rate. This translational upregulation of GATA-3 is dependent on TCR signaling through the PI3K/mTOR pathway and our preliminary data indicate that this is mediated through RNA secondary structure within the 5'UTR. These observations suggest a model of translational regulation where TCR signaling enhances the activity of the eIF2A helicase, which is required for ribosome scanning through 5'UTR with stable secondary structures. The overall aims of this proposal are to map the cis element in the GATA-3 5'UTR and to identify the downstream signaling pathways that regulate GATA-3 translation rate. The overall goal of these studies will be to identify specific molecular targets within GATA-3 that impact on the generation and stability of Th2 effectors cells and that could be developed into experimental modalities to control atopic diseases, including asthma.