Browsing by Author "Rutan, Caleb D."

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    A Translational Regulatory Mechanism Mediated by Hypusinated Eukaryotic Initiation Factor 5A Facilitates β-Cell Identity and Function
    (American Diabetes Association, 2024) Connors, Craig T.; Villaca, Catharina B. P.; Anderson-Baucum, Emily K.; Rosario, Spencer R.; Rutan, Caleb D.; Childress, Paul J.; Padgett, Leah R.; Robertson, Morgan A.; Mastracci, Teresa L.; Biology, School of Science
    As professional secretory cells, β-cells require adaptable mRNA translation to facilitate a rapid synthesis of proteins, including insulin, in response to changing metabolic cues. Specialized mRNA translation programs are essential drivers of cellular development and differentiation. However, in the pancreatic β-cell, the majority of factors identified to promote growth and development function primarily at the level of transcription. Therefore, despite its importance, the regulatory role of mRNA translation in the formation and maintenance of functional β-cells is not well defined. In this study, we have identified a translational regulatory mechanism mediated by the specialized mRNA translation factor eukaryotic initiation factor 5A (eIF5A), which facilitates the maintenance of β-cell identity and function. The mRNA translation function of eIF5A is only active when it is posttranslationally modified ("hypusinated") by the enzyme deoxyhypusine synthase (DHPS). We have discovered that the absence of β-cell DHPS in mice reduces the synthesis of proteins critical to β-cell identity and function at the stage of β-cell maturation, leading to a rapid and reproducible onset of diabetes. Therefore, our work has revealed a gatekeeper of specialized mRNA translation that permits the β-cell, a metabolically responsive secretory cell, to maintain the integrity of protein synthesis necessary during times of induced or increased demand.
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    Deciphering the Role of Eukaryotic Initiation Factor 5A in Pancreatic Organogenesis
    (2024-08) Rutan, Caleb D.; Mastracci, Teresa L.; Berbari, Nicolas F.; Balakrishnan, Lata N.; Roh, Hyun Cheol
    The pancreas is composed of a variety of cell types such as acinar, endocrine, and ductal cells, as well as endothelial cells and adipocytes. Whereas we understand the distinct functions of each, there remains an incomplete understanding of the molecular pathways and communications that exist between these cells that may influence development, growth, and function. Given that diabetes is characterized by the destruction or dysfunction of the insulin-producing pancreatic beta cell, a better understanding of the mechanisms that influence cell growth and maintenance in the pancreas is of therapeutic interest. Genome-wide association studies identified eukaryotic initiation factor 5A (eIF5A) to be within a type 1 diabetes susceptibility locus, which also suggests this translation factor may play a role in maintaining beta cell health. EIF5A is active once post-translationally modified by the rate-limiting enzyme deoxyhypusine synthase (DHPS) in a process known as hypusination, producing hypusinated eIF5A (eIF5AHYP). The functional loss of eIF5AHYP via pancreas-specific genetic deletion of Dhps or Eif5a within multipotent pancreatic progenitor cells (MPPCs) results in an mRNA translation defect detectable at E14.5 causing the decreased expression of many proteins required for exocrine growth and function. Moreover, DHPSΔPANC mice die by 6 weeks-of-age; however, eIF5AΔPANC mice survive up to 2 years-of-age. The postnatal phenotype of the eIF5AΔPANC model was investigated in this thesis.