Diabetes mellitus and exocrine pancreatic dysfunction in perk-/- mice reveals a role for translational control in secretory cell survival.
The protein kinase PERK couples protein folding in the endoplasmic reticulum (ER) to polypeptide biosynthesis by phosphorylating the alpha subunit of eukaryotic translation initiation factor 2 (eIF2alpha), attenuating translation initiation in response to ER stress. PERK is highly expressed in mouse pancreas, an organ active in protein secretion. Under physiological conditions, PERK was partially activated, accounting for much of the phosphorylated eIF2alpha in the pancreas. The exocrine and endocrine pancreas developed normally in Perk-/- mice. Postnatally, ER distention and activation of the ER stress transducer IRE1alpha accompanied increased cell death and led to progressive diabetes mellitus and exocrine pancreatic insufficiency. These findings suggest a special role for translational control in protecting secretory cells from ER stress.
Harding
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HP
Skirball Institute of Biomolecular Medicine, New York University School of Medicine, 10016, New York, NY, USA.
Zeng
H
H
Zhang
Y
Y
Jungries
R
R
Chung
P
P
Plesken
H
H
Sabatini
D D
DD
Ron
D
D
D000818:Animals; D016923:Cell Death / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000201:enzymology / Q000648:ultrastructure; D005260:Female; D005934:Glucagon / Q000032:analysis; D006943:Hyperglycemia / Q000378:metabolism; D020287:In Situ Nick-End Labeling; D007328:Insulin / Q000032:analysis / Q000097:blood / Q000235:genetics; D007515:Islets of Langerhans / Q000737:chemistry / Q000166:cytology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008854:Microscopy, Electron; D010179:Pancreas / Q000166:cytology / Q000201:enzymology* / Q000378:metabolism; D010641:Phenotype; D010766:Phosphorylation; D011384:Proinsulin / Q000378:metabolism; D014176:Protein Biosynthesis / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis; D022142:Secretory Vesicles / Q000378:metabolism; D019892:eIF-2 Kinase / Q000235:genetics* / Q000378:metabolism*
D005934:Glucagon; D007328:Insulin; D011384:Proinsulin; D012333:RNA, Messenger; D019892:eIF-2 Kinase