Research
Our research aims to explore the role and regulation of protein synthesis in normal and diseased states. Protein synthesis is a complex system that ensures organismal homeostasis by controlling the quantity and quality of the proteome. Regulation of gene expression at the translational level provides a temporal advantage by eliciting rapid fluctuations in protein levels in response to changes in the cellular environment. Protein synthesis is one of the most energy demanding processes in the cell and the high energy cost of protein production requires the cell to closely monitor and regulate the translational machinery to ensure proper growth and survival under conditions of stress. In response to diverse physiological and pathological states, several signaling pathways are activated that converge on the translational machinery to alter the rates and types of protein being synthesized. The pervasiveness of translational control is evident in the genesis and progression of diseases such as cancer, neruodegeneration, and infections that are often a consequence of deregulated protein synthesis. Such deregulation presents an excellent opportunity to selectively target the translational machinery for therapeutic advancement.
Regulation of eukaryotic translation initiation factors (eIFs)
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Eukaryotic protein synthesis is predominantly regulated at the initiation stage. Translation is initiated by the recognition of the 5' cap (or IRES) of mRNA followed by the recruitment of the 40S ribosomal subunit onto mRNA and start codon recognition. These key steps in initiation are tightly controlled by the eIFs and are also influenced by elements in the 5'UTR, ORF and 3'UTR of individual mRNAs. Based on the cellular context, upstream signaling pathways regulate eIFs by altering their levels, or their activities via post-translational modifications such as methylation, phosphorylation or by reorganizing their spatial distribution. Our recent work has identified novel post-translational modifications of eIFs that is dependent on the state of growth or stress . We are currently exploring the role of these post-translational modifications in altering eIFs function in initiating global translation or translation of selective mRNAs and their influence on cellular growth and survival.
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Overview of Eukaryotic Translation Initiation
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Translational Control of Cancer
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Since the 1800s, enlarged nucleoli are considered a hallmark of cancer cells. Enlarged nucleoli serve as hubs of enhanced ribosome biogenesis, thereby leading to increased production of proteins that sustain the uncontrolled growth and proliferation of cancer cells. Our research is focused on understanding the contributions of translational control towards tumor initiation and progression towards malignancy. We are currently investigating the interplay of oncogenes and tumor suppressors in regulating eIFs and other translational factors. These efforts will help to identify novel targets that will eventually provide parallel or alternate means for cancer therapeutics.
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Protein Synthesis and Stem cells
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Adult stem cells are essential for maintaining tissue integrity by serving as a renewed source of cells. Interestingly, most adult stem cells exhibit lower rates of protein synthesis compared to their progenitor cells. It is unclear as to how such low rates of protein synthesis are maintained in stem cells and how they influence the stem cell response to stress. Protein synthesis regulation in adult stem cells in vastly under explored. We are interested in understanding the mechanisms that regulate the translation initiation machinery and influence the protein synthesis rates in adult stem cells. Our efforts are aimed at understanding the fundamental biology of adult stem cells, which will help to expand the application of stem cells in regenerative medicine, and for treatment of cancer and other diseases.
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Murine stem cell-enriched spheroids expressing GFP
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Department of Biological Sciences, Wehr Life Science, Marquette University, Milwaukee, WI-53217