Post-transcriptional regulation of gene expression by the Y-box factor ZONAB and cell survival

Y-box 因子 ZONAB 对基因表达的转录后调控和细胞存活

• 批准号: BB/H002294/1
• 负责人: Karl Matter
• 金额: $ 52.03万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2009
• 资助国家: 英国
• 起止时间: 2009 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FH002294%2F1
• 关键词: Post; transcriptional; regulation; gene; expression

Epithelia are continuous layers of cells that delineate our tissues and organs. Individual epithelial cells interact with each other via molecular complexes that mediate adhesion but also function as sensors that transmit information about the environment, such as the presence or absence of neighbouring cells, to the cell interior. Integrity of epithelia is important for our organs to function normally and to protect us from our environment. For example, breaches in epithelial layers such as the skin or in the lining of the intestine can lead to serious infections. Epithelial cells thus need molecular mechanisms that ensure proper responses to environmental and cellular factors that would otherwise lead to cell death and tissue damage. This proposal focuses on such a mechanism that is based on a protein that regulates expression of genes. Genes are part of the genome in the nucleus of cells, and encode the proteins that make up our cells and tissues. Genes are first transcribed into an mRNA, a messenger molecule that carries the information to the cellular machinery that synthesizes the proteins. Expression of genes can thus be regulated at different levels: transcription to mRNA, transport and stability of mRNA, and protein synthesis. Our experiments focus on a new mechanism by which epithelial cells respond to stress conditions to regulate the stability of mRNA and/or protein synthesis. This mechanism is important for cell survival as inactivation results in cell death in response to stress. The main component of this mechanism is a molecule that is regulated by adhesion complexes between cells as well as regulatory pathways known to be important for cellular responses. Our aims are to identity the molecular mechanisms by which this central component binds to mRNA and how this is stimulated by different stress conditions. We also want to determine which cellular components are directly affected as well as the importance of such components for cell survival. Understanding how cells respond to stress and how they ensure survival is important for our understanding of how tissues and organs form and maintain themselves. Many diseases such as infections and cancer as well as environmental toxins cause cellular stress and understanding how cells respond will help us to design new therapies. In some cases, cell death is the goal of a therapy, as it is in the case of chemotherapy to fight cancer. Hence, identifying mechanisms that keep cells alive will also aid the development of approaches to increase the efficiencies of existing therapies by targeting such mechanisms in combination with chemotherapy.

上皮细胞是连续的细胞层，划分我们的组织和器官。单个上皮细胞通过介导粘附的分子复合物相互作用，但也作为传感器将有关环境的信息（如邻近细胞的存在或不存在）传递到细胞内部。上皮的完整性对于我们的器官正常运作和保护我们免受环境的影响是很重要的。例如，皮肤等上皮层或肠道内壁的破裂可能导致严重的感染。因此，上皮细胞需要分子机制来确保对环境和细胞因素做出适当的反应，否则会导致细胞死亡和组织损伤。这一建议着重于这样一种机制，它是基于一种调节基因表达的蛋白质。基因是细胞核基因组的一部分，编码构成我们细胞和组织的蛋白质。基因首先被转录成mRNA，这是一种信使分子，它将信息传递给合成蛋白质的细胞机器。因此，基因的表达可以在不同的水平上进行调节：转录到mRNA， mRNA的转运和稳定性，以及蛋白质合成。我们的实验集中在一个新的机制，上皮细胞响应应激条件来调节mRNA和/或蛋白质合成的稳定性。这种机制对于细胞存活是重要的，因为失活导致细胞在应激反应中死亡。该机制的主要组成部分是一种受细胞间粘附复合物调节的分子，以及已知对细胞反应重要的调节途径。我们的目标是确定这一核心成分与mRNA结合的分子机制，以及不同应激条件下如何刺激这一机制。我们还想确定哪些细胞成分直接受到影响，以及这些成分对细胞存活的重要性。了解细胞如何应对压力以及它们如何确保生存，对于我们理解组织和器官如何形成和维持自身非常重要。许多疾病，如感染和癌症以及环境毒素都会引起细胞应激，了解细胞如何反应将有助于我们设计新的治疗方法。在某些情况下，细胞死亡是治疗的目标，就像化疗对抗癌症一样。因此，确定维持细胞存活的机制也将有助于开发新的方法，通过靶向这些机制与化疗相结合来提高现有疗法的效率。

项目成果

Identification of MarvelD3 as a tight junction-associated transmembrane protein of the occludin family.

• DOI: 10.1186/1471-2121-10-95
• 发表时间: 2009-12-22
• 期刊: BMC cell biology
• 作者: Steed E;Rodrigues NT;Balda MS;Matter K
• 通讯作者: Matter K

Lowe Syndrome protein OCRL1 supports maturation of polarized epithelial cells.

• DOI: 10.1371/journal.pone.0024044
• 发表时间: 2011
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Grieve AG;Daniels RD;Sanchez-Heras E;Hayes MJ;Moss SE;Matter K;Lowe M;Levine TP
• 通讯作者: Levine TP

Epithelial junction formation requires confinement of Cdc42 activity by a novel SH3BP1 complex.

• DOI: 10.1083/jcb.201202094
• 发表时间: 2012-08-20
• 期刊: The Journal of cell biology
• 作者: Elbediwy A;Zihni C;Terry SJ;Clark P;Matter K;Balda MS
• 通讯作者: Balda MS