The re-modelling of mRNPs and the regulation of localised mRNA translation during mammalian cell attachment and spreading

哺乳动物细胞附着和扩散过程中 mRNP 的重塑和局部 mRNA 翻译的调节

• 批准号: BB/L018209/1
• 负责人: Simon Morley
• 金额: $ 42.22万
• 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: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FL018209%2F1
• 关键词: re; modelling; mRNPs; regulation; localised

During cell migration, critical information stored in the genetic material (DNA) has to be decoded by the cell to produce a wide variety of proteins in the right amount, place and time to allow for this process occur; tumour cells often get this wrong! 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. Regulatory proteins, such as 4E-BP1 and CYFIP, prevent the interaction of eIF4E with the scaffold protein, eIF4G, and stop the recruitment of mRNA to the ribosome and halt protein synthesis. When protein synthesis is needed, the cell signals for the release the eIF4E/mRNA from the inhibited complex to let it work when and where it is needed. However, we still do not know how the cell controls exactly where protein synthesis is activated in cells which are in the process of spreading and migrating. From "looking" inside the cell with specialised microscopy techniques, we know that the initiation factors and their regulatory proteins are discretely localised to the edge of cells in the direction that they are moving; they are not just floating about. In the work described here we want to investigate the nature of the specialised signals used by the cell to regulate localised protein synthesis, look at the complexes of proteins and mRNA found at such sites and understand what parts of the mRNA make it attractive to these mRNA binding proteins at the edge of cells.These studies will substantially increase our general understanding of the significance of the control of protein synthesis in the regulation of cell growth and migration, opening up new potential avenues for controlling cancer cells which have acquired the ability to move about the body.

在细胞迁移期间，必须将存储在遗传材料（DNA）中的关键信息被细胞解码，以在适当的，地点和时间以适当的时间产生多种蛋白质，以实现此过程。肿瘤细胞常常弄错了！信息从DNA到蛋白质的一般传递是由Messenger RNA（mRNA）进行的，该元素是DNA序列的副本。该mRNA必须在称为翻译的过程中通过称为核糖体的复杂的，高度调节的机器将其解码为蛋白质。要高效，准确地工作并允许核糖体为细胞的最大利益发挥作用，该机械需要相互相互作用的辅助蛋白（翻译起始因子； EIF），并确保mRNA和核糖体发生共同制成高度调节的大型启动复合物，以使所需的蛋白质。那么细胞如何控制这个呢？ 起始因子本身的相互作用本身是哺乳动物细胞调节的主要部位。调节蛋白，例如4E-BP1和CYFIP，可以防止EIF4E与支架蛋白，EIF4G的相互作用，并阻止mRNA募集到核糖体和停止蛋白质合成中。当需要蛋白质合成时，释放eIF4E/mRNA的细胞信号从抑制的复合物中，以便在需要时和何处起作用。但是，我们仍然不知道细胞如何准确控制蛋白质合成在扩散和迁移过程中的细胞中激活的位置。从具有专门显微镜技术的细胞内部的“看”，我们知道，起始因子及其调节蛋白在其移动方向上离散地定位于细胞边缘。他们不只是漂浮。在此处描述的工作中，我们想研究细胞用于调节局部蛋白质合成的专门信号的性质，查看在此类位点发现的蛋白质和mRNA的复合物，并了解mRNA的哪些部分使其对这些mRNA有吸引力这些研究将大大提高我们对蛋白质合成在细胞生长和迁移调节中的控制意义的一般理解，从关于身体。

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

The S. pombe translation initiation factor eIF4G is Sumoylated and associates with the SUMO protease Ulp2.

• DOI: 10.1371/journal.pone.0094182
• 发表时间: 2014
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Jongjitwimol J;Feng M;Zhou L;Wilkinson O;Small L;Baldock R;Taylor DL;Smith D;Bowler LD;Morley SJ;Watts FZ
• 通讯作者: Watts FZ

Sumoylation of eIF4A2 affects stress granule formation.

• DOI: 10.1242/jcs.184614
• 发表时间: 2016-06-15
• 期刊: Journal of cell science
• 影响因子: 4
• 作者: Jongjitwimol J;Baldock RA;Morley SJ;Watts FZ
• 通讯作者: Watts FZ

The helicase, DDX3X, interacts with poly(A)-binding protein 1 (PABP1) and caprin-1 at the leading edge of migrating fibroblasts and is required for efficient cell spreading.

• DOI: 10.1042/bcj20170354
• 发表时间: 2017-08-30
• 期刊: The Biochemical journal
• 作者: Copsey AC;Cooper S;Parker R;Lineham E;Lapworth C;Jallad D;Sweet S;Morley SJ
• 通讯作者: Morley SJ

Synergistic effects of inhibiting the MNK-eIF4E and PI3K/AKT/ mTOR pathways on cell migration in MDA-MB-231 cells.

• DOI: 10.18632/oncotarget.24354
• 发表时间: 2018-03-06
• 期刊: Oncotarget
• 作者: Lineham E;Tizzard GJ;Coles SJ;Spencer J;Morley SJ
• 通讯作者: Morley SJ