PERK is required in the adult pancreas and is essential for maintenance of glucose homeostasis
| Autor: | Daniel J. Sartori, Yan Gao, Qian-Chun Yu, Jake A. Kushner, J. Alan Diehl, M. Celeste Simon, Changhong Li |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
medicine.medical_specialty
Programmed cell death endocrine system Endoplasmic Reticulum Diabetes mellitus genetics Gene Knockout Techniques Islets of Langerhans Mice eIF-2 Kinase Cyclin D1 Internal medicine Insulin-Secreting Cells medicine Diabetes Mellitus Glucose homeostasis Animals Homeostasis RNA Messenger Molecular Biology Pancreas Cell Proliferation Mice Knockout geography geography.geographical_feature_category biology Base Sequence Cell growth Cell Biology Articles Islet Endocrinology Glucose Hyperglycemia biology.protein Unfolded protein response Unfolded Protein Response GLUT2 |
| Zdroj: | Molecular and cellular biology. 32(24) |
| ISSN: | 1098-5549 |
| Popis: | 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 β 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 β cell death, this was not a result of decreased proliferation as previously reported. In contrast, a significant and specific increase in β 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 β cell survival in adult mice. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|