Regulation of mRNA Translation During Cellular Stress and Apoptosis

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The process of gene expression is tightly regulated at various levels including transcriptional, translational and post-translational steps. The regulation of gene expression at the translational level allows cells to rapidly reprogram protein output in response to stress stimuli. During stress conditions, global mRNA translation (canonical translation) is reduced due to modification of key eukaryotic translation initiation factors (eIFs). However, the alternative means of translation initiation (non-canonical translation) allow production of proteins that are required to manage stress conditions. For example, the production of both pro-survival and pro-death proteins is regulated via non-canonical translation mechanisms. Thus, the non-canonical translation is considered to play a central role during cellular stress. The long-term goal of my research program is to understand how non-canonical translation impacts the balance between cellular homeostasis and cell death during stress conditions. Internal ribosome entry site (IRES)-mediated translation is one of the validated non-canonical translation initiation mechanisms that operates under stress conditions. The production of many proteins that affect cell death is regulated by an IRES-dependent mechanism. Extensive evidence suggests that IRES-mediated translation of cellular mRNAs greatly relies on IRES trans-acting factors (ITAFs). However, the mechanisms of cellular IRESes and ITAFs during expression of stress-related proteins are poorly defined. In Objective 1 of this proposal, I will investigate the mechanism of IRES- and ITAFs-mediated translation of cellular mRNAs during stress conditions. Upstream open reading frame (uORF)-dependent translation initiation is another non-canonical translation initiation mechanism used under stress conditions. Key proteins, which play critical roles in cell cycle regulation and cell death, are translationally regulated by the uORF-dependent mechanism. It remains unknown if eIFs play a role in cell cycle regulation and cell death by modulating translation of uORFs-containing mRNAs. In Objective 2, I will define the role of one eIF (eIF5B) for uORF-dependent translation in cell cycle and cell death. My research program will provide significant insight into the process of mRNA translation. The knowledge generated will be applicable to the molecular biology research areas of development, differentiation, and metamorphosis. Moreover, this proposed study will provide clues toward understanding the relevance of dysregulated mRNA translation in various physiological disorders such as cancer, and Alzheimer's disease. My research program will provide state-of-the-art skills to my trainees in cellular and molecular biology as well as biochemistry research areas and prepare them for employment in academia, public sector, and the growing RNA-based industry.