Journal
MOLECULAR AND CELLULAR BIOLOGY
Volume 32, Issue 24, Pages 5129-5139Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.01009-12
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Funding
- National Institutes of Health [P01 CA104838]
- Leukemia & Lymphoma Scholar award
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Germ line PERK mutations are associated with diabetes mellitus and growth retardation in both rodents and humans. In contrast, late embryonic excision of PERK permits islet development and was found to prevent onset of diabetes, suggesting that PERK may be dispensable in the adult pancreas. To definitively establish the functional role of PERK in adult pancreata, we generated mice harboring a conditional PERK allele in which excision is regulated by tamoxifen administration. Deletion of PERK in either young adult or mature adult mice resulted in hyperglycemia associated with loss of islet and beta cell architecture. PERK excision triggered intracellular accumulation of proinsulin and Glut2, massive endoplasmic reticulum (ER) expansion, and compensatory activation of the remaining unfolded-protein response (UPR) signaling pathways specifically in pancreatic tissue. Although PERK excision increased beta cell death, this was not a result of decreased proliferation as previously reported. In contrast, a significant and specific increase in beta cell proliferation was observed, a result reflecting increased cyclin D1 accumulation. This work demonstrates that contrary to expectations, PERK is required for secretory homeostasis and beta cell survival in adult mice.
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