Abstract
We have recently shown that silencing of the brain/islet specific c-Jun N-terminal Kinase3 (JNK3) isoform enhances both basal and cytokine-induced beta-cell apoptosis, whereas silencing of JNK1 or JNK2 has opposite effects. While it is known that JNK1 or JNK2 may promote apoptosis by inhibiting the activity of the pro-survival Akt pathway, the effect of JNK3 on Akt has not been documented. This study aims to determine the involvement of individual JNKs and specifically JNK3 in the regulation of the Akt signaling pathway in insulin-secreting cells. JNK3 silencing strongly decreases Insulin Receptor Substrate 2 (IRS2) protein expression, and blocks Akt2 but not Akt1 activation by insulin, while the silencing of JNK1 or JNK2 activates both Akt1 and Akt2. Concomitantly, the silencing of JNK1 or JNK2, but not of JNK3, potently phosphorylates the glycogen synthase kinase3 (GSK3β). JNK3 silencing also decreases the activity of the transcription factor Forkhead BoxO3A (FoxO3A) that is known to control IRS2 expression, in addition to increasing c-Jun levels that are known to inhibit insulin gene expression. In conclusion, we propose that JNK1/2 on one hand and JNK3 on the other hand, have opposite effects on insulin-signaling in insulin-secreting cells; JNK3 protects beta-cells from apoptosis and dysfunction mainly through maintenance of a normal IRS2 to Akt2 signaling pathway. It seems that JNK3 mediates its effects mainly at the transcriptional level, while JNK1 or JNK2 appear to mediate their pro-apoptotic effect in the cytoplasm.
Highlights
Sustained pancreatic beta-cell death, which mainly occurs by apoptosis, leads to diabetes mellitus [1,2,3]
Insulin Receptor Substrate 2 (IRS2) promotes beta-cell growth and survival and we have shown that cells with reduced Jun N-terminal Kinase3 (JNK3) expression undergo spontaneous apoptosis [12]
INS-1E cells were transfected with Small interfering RNA (siRNA) targeting selectively each one of the three individual Jnks and RNA and protein extracts were prepared for RT-PCR and western blot analysis
Summary
Sustained pancreatic beta-cell death, which mainly occurs by apoptosis, leads to diabetes mellitus [1,2,3]. JNK1 and JNK2 are ubiquitously expressed, while JNK3 was found to be restricted to the brain and testis [10,11]; we recently described high expression and functional role of this isoform in pancreatic islet cells [12]. Despite their high structural homology, the JNK isoforms have distinct biological functions. While Jnk knockout animals have not been studied for metabolic disorders, we provided evidence that JNK3 is protective against cytokine-induced apoptosis in an insulin-secreting cell line [12]
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