Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:The MAPK kinase kinase-1 is essential for stress-induced pancreatic islet cell death. 1830 48

Elevated IL-12 production and higher rate of CD4(+) T conventional (Tconv) cell proliferation in NOD mice have been implicated in the progression of type 1 diabetes. However, the underlying mechanisms remain largely unknown, even though enhanced activation of the IkappaB kinase (IKK)/NF-kappaB pathway has been revealed to mediate IL-12 overproduction. In this study, we report that deviated p38 MAPK activation also contributes to elevated IL-12 production with a mechanism involving MAPK-activated protein kinase-2-mediated stabilization of IL-12p40 mRNA. Aberrant p38 activation induced by various inflammatory stimuli in IL-12-overproducing cells is not due to defective MAPK phosphatase-1 induction in NOD mice. Deviated IKK and MAPKs activation also occurs in NOD CD4(+) Tconv cells, which is associated with higher rates of proliferation. All of the above evidence suggests that the signaling defects occur at the level of MAPK kinase kinase (MAK3K or MEKK). Further exploration shows that MEKK3, but not other MAP3Ks, is overexpressed in NOD IL-12-overproducing cells and CD4(+) Tconv cells independent of autoimmune inflammation. MEKK3 knockdown leads to reversal of the deviated IKK and MAPKs activation, resulting in reduced IL-12 production and decreased CD4(+) Tconv cell proliferation. Thus, this study provides a molecular mechanism of the hyperresponsiveness of IL-12-overproducing cells and CD4(+) Tconv cells in NOD mice.
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PMID:MEKK3 overexpression contributes to the hyperresponsiveness of IL-12-overproducing cells and CD4+ T conventional cells in nonobese diabetic mice. 2072 Feb 1