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.

在细胞迁移过程中，存储在遗传物质 (DNA) 中的关键信息必须由细胞解码，以在正确的数量、地点和时间产生多种蛋白质，以实现这一过程的发生；肿瘤细胞经常犯这个错误！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 和核糖体结合成一个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。调节蛋白（例如 4E-BP1 和 CYFIP）可防止 eIF4E 与支架蛋白 eIF4G 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，细胞发出信号，要求从受抑制的复合物中释放 eIF4E/mRNA，使其在需要的时间和地点发挥作用。然而，我们仍然不知道细胞如何准确控制细胞中蛋白质合成在扩散和迁移过程中被激活的位置。通过使用专门的显微镜技术“观察”细胞内部，我们知道启动因子及其调节蛋白沿着细胞移动的方向离散地定位于细胞边缘；它们不只是漂浮着。在这里描述的工作中，我们想要研究细胞用来调节局部蛋白质合成的特殊信号的性质，观察在这些位点发现的蛋白质和 mRNA 的复合物，并了解 mRNA 的哪些部分使其对细胞边缘的这些 mRNA 结合蛋白具有吸引力。这些研究将大大增加我们对控制蛋白质合成在调节细胞生长和迁移中的重要性的一般理解，为 控制已获得在体内移动能力的癌细胞。

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.

解旋酶DDX3X在迁移成纤维细胞的前沿与poly（a）结合蛋白1（PABP1）和Caprin-1相互作用，对于有效的细胞扩散是必需的。

• 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

Probing the Anticancer Action of Novel Ferrocene Analogues of MNK Inhibitors.

• DOI: 10.3390/molecules23092126
• 发表时间: 2018-08-23
• 期刊: Molecules (Basel, Switzerland)
• 作者: Sansook S;Lineham E;Hassell-Hart S;Tizzard GJ;Coles SJ;Spencer J;Morley SJ
• 通讯作者: Morley SJ