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

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.

Maintenance of epithelial integrity is a fundamental process required for normal organ function. Epithelial cells adhere to each other via junctional complexes, enabling them to form cellular barriers that separate different tissues and body compartments. Tight junctions are one of these intercellular junctions and restrict paracellular permeability. Tight junctions also contribute to the regulation of epithelial proliferation and differentiation via different types of signalling mechanisms. This proposal is based on ZONAB/DbpA, a Y-box transcription factor that is regulated by the tight junction protein ZO-1 as well as other upstream signalling pathways such as RalA/Ras. ZONAB functions as a transcription factor in proliferating cells. Our preliminary data now suggest that ZONAB also serves as a central component of a posttranscriptional regulatory mechanism that is important for cell survival and regulates the expression of important cellular regulatory proteins. Our aims thus are to determine how ZONAB interacts with specific mRNAs, how ZONAB becomes activated in response to specific stress conditions and which of its known upstream regulators is involved in activation, and to analyse functionally relevant posttranscriptional ZONAB targets on a genome-wide scale. The expected results will be important for the understanding of how epithelial cells respond to stress and how posttranscriptional regulation of gene expression contributes to epithelial homeostasis.