The MAPK kinase kinase-1 is essential for stress-induced pancreatic islet cell death.
The aim of the present investigation was to characterize the role of the MAPK kinase kinase-1 (MEKK-1) in stress-induced cell death of insulin producing cells. We observed that transient overexpression of the wild type MEKK-1 protein in the insulin-producing cell lines RIN-5AH and betaTC-6 increased c-Jun N-terminal kinase (JNK) phosphorylation and augmented cell death induced by diethylenetriamine/nitroso-1-propylhydrazino)-1-propanamine (DETA/NO), streptozotocin (STZ), and hydrogen peroxide (H2O2). Furthermore, DETA/NO or STZ induced a rapid threonine phosphorylation of MEKK-1. Silencing of MEKK-1 gene expression in betaTC-6 and human dispersed islet cells, using in vitro-generated diced small interfering RNA, resulted in protection from DETA/NO, STZ, H2O2, and tunicamycin induced cell death. Moreover, in DETA/NO-treated cells diced small interfering RNA-mediated down-regulation of MEKK-1 resulted in decreased activation of JNK but not p38 and ERK. Inhibition of JNK by treatment with SP600125 partially protected against DETA/NO- or STZ-induced cell death. In summary, our results support an essential role for MEKK-1 in JNK activation and stress-induced beta-cell death. Increased understanding of the signaling pathways that augment or diminish beta-cell MEKK-1 activity may aid in the generation of novel therapeutic strategies in the treatment of type 1 diabetes.
Mokhtari
Dariush
D
Department of Medical Cell Biology, Uppsala University, Biomedicum, S-751 23 Uppsala, Sweden.
Myers
Jason W
JW
Welsh
Nils
N
D000818:Animals; D016923:Cell Death; D002470:Cell Survival; D003922:Diabetes Mellitus, Type 1 / Q000628:therapy; D005434:Flow Cytometry; D017930:Genes, Reporter; D006801:Humans; D007340:Insulinoma / Q000201:enzymology / Q000473:pathology; D007515:Islets of Langerhans / Q000166:cytology / Q000201:enzymology*; D048728:MAP Kinase Kinase Kinase 1 / Q000235:genetics / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D015398:Signal Transduction; D014162:Transfection; D014407:Tumor Cells, Cultured
D012333:RNA, Messenger; D034741:RNA, Small Interfering; D048728:MAP Kinase Kinase Kinase 1