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.

在肌肉细胞再生或受伤后，细胞必须对遗传物质 (DNA) 基因序列中存储的关键信息进行解码，以产生正确类型和适量的多种必需蛋白质，以实现这一目标。过程。从 DNA 到蛋白质的一般信息传递是由信使 RNA (mRNA) 执行的，它是 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（称为核糖体）解码为蛋白质，这一过程称为翻译。为了高效、准确地工作，并让核糖体按照细胞的最佳利益发挥作用，这一机制需要相互相互作用的辅助蛋白（翻译起始因子；eIF），并确保 mRNA 和核糖体相互结合。一起形成高度调控的大型起始复合物以产生所需的蛋白质。那么细胞是如何控制这一点的呢？起始因子本身的相互作用是哺乳动物细胞中调节的主要位点。一种蛋白质 4E 结合蛋白 1 (4E-BP1) 可阻止 eIF4E 与支架蛋白 eIF4G 的相互作用，并阻止 mRNA 募集到核糖体并停止蛋白质合成。当需要蛋白质合成时，细胞向 4E-BP1 发出信号，从 4E-BP1/eIF4E/mRNA 复合物中释放 eIF4E/mRNA，使其发挥作用。细胞通过磷酸化过程用磷酸基团标记 4E-BP1 来实现这一点。这种修饰促进其从 eIF4E/mRNA 中释放，随后 eIF4E/mRNA 可以与 eIF4G 结合，并形成生成肌肉细胞再生所需的正确类型和数量的蛋白质所需的多蛋白起始复合物。在这里描述的工作中，我们想要研究引起 4E-BP1 磷酸化所需的信号，并确定对于控制肌肉细胞再生过程中这一过程非常重要的标记位点。我们还想更多地了解组装 4E-BP1/eIF4E/mRNA 复合物中储存形式的 mRNA 需要哪些其他细胞成分。

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