IB1 reduces cytokine-induced apoptosis of insulin-secreting cells.
IB1/JIP-1 is a scaffold protein that interacts with upstream components of the c-Jun N-terminal kinase (JNK) signaling pathway. IB1 is expressed at high levels in pancreatic beta cells and may therefore exert a tight control on signaling events mediated by JNK in these cells. Activation of JNK by interleukin 1 (IL-1beta) or by the upstream JNK constitutive activator DeltaMEKK1 promoted apoptosis in two pancreatic beta cell lines and decreased IB1 content by 50-60%. To study the functional consequences of the reduced IB1 content in beta cell lines, we used an insulin-secreting cell line expressing an inducible IB1 antisense RNA that lead to a 38% IB1 decrease. Reducing IB1 levels in these cells increased phosphorylation of c-Jun and increased the apoptotic rate in presence of IL-1beta. Nitric oxide production was not stimulated by expression of the IB1 antisense RNA. Complementary experiments indicated that overexpression of IB1 in insulin-producing cells prevented JNK-mediated activation of the transcription factors c-Jun, ATF2, and Elk1 and decreased IL-1beta- and DeltaMEKK1-induced apoptosis. These data indicate that IB1 plays an anti-apoptotic function in insulin-producing cells probably by controlling the activity of the JNK signaling pathway.
Bonny
C
C
Division of Medical Genetics and the Department of Internal Medicine, CHUV University Hospital, 1011 Lausanne Switzerland. christophe.bonny@chuv.hospvd.ch
Oberson
A
A
Steinmann
M
M
Schorderet
D F
DF
Nicod
P
P
Waeber
G
G
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D004318:Doxycycline / Q000494:pharmacology; D005947:Glucose / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007375:Interleukin-1 / Q000494:pharmacology*; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000528:radiation effects; D009569:Nitric Oxide / Q000378:metabolism; D009687:Nuclear Proteins / Q000502:physiology*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D016372:RNA, Antisense / Q000235:genetics; D015534:Trans-Activators / Q000502:physiology*; D014466:Ultraviolet Rays
D007328:Insulin; D007375:Interleukin-1; D009687:Nuclear Proteins; D016372:RNA, Antisense; D015534:Trans-Activators; D009569:Nitric Oxide; D017346:Protein Serine-Threonine Kinases; D005947:Glucose; D004318:Doxycycline