Pancreatic beta-cell failure and diabetes in mice with a deletion mutation of the endoplasmic reticulum molecular chaperone gene P58IPK.
The endoplasmic reticulum (ER) transmits apoptotic signals in the pancreas during ER stress, implicating ER stress-mediated apoptosis in the development of diabetes. P58(IPK) (DNAJC3) is induced during ER stress and functions as a negative feedback component to inhibit eIF-2alpha signaling and attenuate the later phases of the ER stress response. To gain insight into a more comprehensive role of P58(IPK) function, we generated deletion mutant mice that showed a gradual onset of glucosuria and hyperglycemia associated with increasing apoptosis of pancreatic islet cells. Lack of P58(IPK) had no apparent effect on the functional integrity of viable beta-cells. A set of genes associated with apoptosis showed altered expression in pancreatic islets from P58(IPK)-null mice, further substantiating the apoptosis phenotype. The data provide in vivo evidence to support the concept that P58(IPK) functions as a signal for the downregulation of ER-associated proteins involved in the initial ER stress response, thus preventing excessive cell loss by degradation pathways. Insulin deficiency associated with the absence of P58(IPK) mimics beta-cell failure associated with type 1 and late-stage type 2 diabetes. P58(IPK) function and activity may therefore provide a novel area of investigation into ER-mediated mechanistic and therapeutic approaches for diabetes.
Ladiges
Warren C
WC
Department of Comparative Medicine, Comparative Mouse Genomics Center, University of Washington, Seattle, Washington 98195, USA. wladiges@u.washington.edu <wladiges@u.washington.edu>
Knoblaugh
Sue E
SE
Morton
John F
JF
Korth
Marcus J
MJ
Sopher
Bryce L
BL
Baskin
Carole R
CR
MacAuley
Alasdair
A
Goodman
Alan G
AG
LeBoeuf
Renee C
RC
Katze
Michael G
MG
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D003920:Diabetes Mellitus / Q000235:genetics / Q000503:physiopathology*; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000502:physiology*; D005260:Female; D006029:Glycosuria; D050956:HSP40 Heat-Shock Proteins; D006943:Hyperglycemia; D007328:Insulin / Q000378:metabolism; D007515:Islets of Langerhans / Q000503:physiopathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018832:Molecular Chaperones / Q000235:genetics / Q000502:physiology*; D009154:Mutation; D012097:Repressor Proteins / Q000235:genetics / Q000502:physiology*; D015854:Up-Regulation
C500846:Dnajc3 protein, mouse; D050956:HSP40 Heat-Shock Proteins; D007328:Insulin; D018832:Molecular Chaperones; D012097:Repressor Proteins