mTOR signalling hyperphosphorylation of 4E-BP1 and translational control during myogenic differentiation

肌原性分化过程中 4E-BP1 的 mTOR 信号过度磷酸化和翻译控制

• 批准号: BB/H009728/1
• 负责人: Simon Morley
• 金额: $ 57.26万
• 依托单位: University of Sussex
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2010
• 资助国家: 英国
• 起止时间: 2010 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FH009728%2F1
• 关键词: mTOR; signalling; hyperphosphorylation; 4E; BP1

During muscle cell regeneration or following injury, critical information stored in the gene sequences of the genetic material (DNA) has to be decoded by the cell to produce a wide variety of essential proteins of the right type and in the right amount to allow for this process. The general transfer of information from DNA to protein is carried out by the messenger RNA (mRNA), which is a copy of the DNA sequence. This mRNA has to be decoded into protein by a complex, highly regulated machine termed a ribosome, in a process known as translation. To work efficiently, accurately, and to allow the ribosome to function in the best interests of the cell, this machinery requires helper proteins (translation initiation factors; eIF) that interact with each other, and also make sure that the mRNA and the ribosome come together into a highly regulated, large initiation complex to make the proteins required. So how does the cell control this? The interaction of the initiation factors themselves is a major site for regulation in mammalian cells. One protein, 4E-binding protein 1 (4E-BP1) prevents the interaction of eIF4E with the scaffold protein, eIF4G, and stops the recruitment of mRNA to the ribosome and halts protein synthesis. When protein synthesis is needed, the cell signals to 4E-BP1 to release the eIF4E/mRNA from the 4E-BP1/eIF4E/mRNA complex to let it work. The cell does this by marking the 4E-BP1 with phosphate groups in a process known as phosphorylation. This modification promotes its release from eIF4E/mRNA which can subsequently bind to eIF4G and form the multi-protein initiation complex required to make the correct types and amounts of protein needed for muscle cell regeneration. In the work described here we want to investigate the signals required to bring about the phosphorylation of 4E-BP1 and identify the tagged sites which are important for controlling this process during muscle cell regeneration. We also want to understand more about what other cellular components are required to assemble the stored forms of mRNA in the 4E-BP1/eIF4E/mRNA complex.

在肌肉细胞再生或损伤后，细胞必须解码存储在遗传物质（DNA）基因序列中的关键信息，以产生各种类型和数量合适的必需蛋白质，以允许这一过程。从DNA到蛋白质的一般信息传递是由信使RNA （mRNA）完成的，信使RNA是DNA序列的副本。这种mRNA必须通过一种复杂的、高度调控的机器——核糖体——解码成蛋白质，这个过程被称为翻译。为了高效、准确地工作，并使核糖体在细胞的最佳利益中发挥作用，这一机制需要相互作用的辅助蛋白（翻译起始因子；eIF），并确保mRNA和核糖体结合成一个高度调节的大型起始复合物，以制造所需的蛋白质。那么细胞是如何控制的呢？起始因子本身的相互作用是哺乳动物细胞调控的主要部位。4e结合蛋白1 （4E-BP1）阻止eIF4E与支架蛋白eIF4G的相互作用，并阻止mRNA向核糖体的募集并停止蛋白质合成。当需要蛋白质合成时，细胞向4E-BP1发出信号，从4E-BP1/eIF4E/mRNA复合体中释放eIF4E/mRNA，使其发挥作用。细胞通过在磷酸化过程中用磷酸基团标记4E-BP1来完成这一过程。这种修饰促进其从eIF4E/mRNA中释放，该mRNA随后可以结合eIF4G并形成多蛋白起始复合物，从而产生肌肉细胞再生所需的正确类型和数量的蛋白质。在这里描述的工作中，我们想要研究导致4E-BP1磷酸化所需的信号，并确定在肌肉细胞再生过程中对控制这一过程很重要的标记位点。我们还想了解更多关于在4E-BP1/eIF4E/mRNA复合体中组装mRNA存储形式所需的其他细胞成分。

项目成果

Murine norovirus 1 (MNV1) replication induces translational control of the host by regulating eIF4E activity during infection.

• DOI: 10.1074/jbc.m114.602649
• 发表时间: 2015-02-20
• 期刊: The Journal of biological chemistry
• 作者: Royall E;Doyle N;Abdul-Wahab A;Emmott E;Morley SJ;Goodfellow I;Roberts LO;Locker N
• 通讯作者: Locker N

mTOR kinase-dependent, but raptor-independent regulation of downstream signaling is important for cell cycle exit and myogenic differentiation.

• DOI: 10.4161/15384101.2014.941747
• 发表时间: 2014
• 期刊: Cell cycle (Georgetown, Tex.)
• 作者: Pollard HJ;Willett M;Morley SJ
• 通讯作者: Morley SJ