Hypusine Biosynthesis in β Cells Links Polyamine Metabolism to Facultative Cellular Proliferation to Maintain Glucose Homeostasis

ABSTRACT: Deoxyhypusine synthase (DHPS) utilizes the polyamine spermidine to catalyze the hypusine modification of the mRNA translation factor eIF5A and promotes oncogenesis through poorly-defined mechanisms. Because germline deletion of Dhps is embryonically lethal, its role in normal postnatal cellular function in vivo remains unknown. We generated a mouse model that allows for inducible, postnatal deletion of Dhps specifically in postnatal islet β cells, which function to maintain glucose homeostasis. Removal of Dhps did not have an effect under normal physiologic conditions. However, upon development of insulin resistance, which induces β-cell proliferation, Dhps deletion caused alterations in proteins required for mRNA translation, reduced production of the cell cycle molecule Cyclin D2, impaired β-cell proliferation, and overt diabetes. We found that hypusine biosynthesis was downstream of protein kinase C-ζ and was required for c-Myc-induced proliferation. Our studies reveal a requirement for DHPS in β cells to link polyamines to mRNA translation to effect facultative cellular proliferation and glucose homeostasis.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Pancreatic Islet

SUBMITTER: Emma Doud  

LAB HEAD: Amber Mosley

PROVIDER: PXD015424 | Pride | 2020-02-17

REPOSITORIES: Pride