Translating into a bigger pancreas

The evolutionarily conserved mRNA translation factor eIF5A is

critical for cell proliferation in developmental and oncogenic
contexts, and its activity depends on hypusination, a
posttranslational modification that is unique to eIF5A. Levasseur
et al. found that eIF5A hypusination was critical for postnatal
expansion of β cell mass in the pancreas. Mice that could not
perform hypusination in β cells did not produce sufficient cyclin
D2 to sustain cell cycling and developed diabetes in response to
diet-induced obesity. Thus, eIF5A hypusination links increased
insulin demand caused by insulin resistance with β cell
proliferation to maintain glucose homeostasis.
Abstract
Deoxyhypusine synthase (DHPS) uses 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 enabled the
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 and protein
secretion, reduced production of the cell cycle molecule cyclin D2,
impaired β cell proliferation, and induced 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.