The MAPK kinase kinase-1 is essential for stress-induced pancreatic islet cell death

Endocrinology. 2008 Jun;149(6):3046-53. doi: 10.1210/en.2007-0438. Epub 2008 Feb 28.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Death
  • Cell Survival
  • Diabetes Mellitus, Type 1 / therapy
  • Flow Cytometry
  • Genes, Reporter
  • Humans
  • Insulinoma / enzymology
  • Insulinoma / pathology
  • Islets of Langerhans / cytology
  • Islets of Langerhans / enzymology*
  • MAP Kinase Kinase Kinase 1 / genetics
  • MAP Kinase Kinase Kinase 1 / metabolism*
  • Polymerase Chain Reaction
  • RNA, Messenger / genetics
  • RNA, Small Interfering / genetics
  • Rats
  • Signal Transduction
  • Transfection
  • Tumor Cells, Cultured


  • RNA, Messenger
  • RNA, Small Interfering
  • MAP Kinase Kinase Kinase 1