We have shown that JNK3, but not JNK1 or JNK2, silencing potently increases c-Jun levels, an effect that is in line with the specific nuclear localization of the kinase; it is therefore conceivable that the decrease in insulin mRNA expression observed in conditions of low JNK3 is mediated through an increase in c-Jun selleck chemicals llc expression and/or stability [12]. In contrast, JNK1 and JNK2 with their mainly cytosolic localization do affect neither c-Jun levels nor insulin expression. With respect to IRS2 expression, it is known that both Irs2 mRNA and protein are short-lived (with mRNA and protein half-lives of 90 min and 2 h, respectively), and thus IRS2 expression appears to be mainly regulated at the transcriptional level [61]; this is fully compatible with a transcriptional regulation of IRS2 by the nuclear JNK3 through regulation of FoxO3A.

These data therefore reinforce our previous hypothesis, that stated that it might be the sub-cellular localizations of the different JNK isoforms that is predominant in governing the cellular response: JNK1 and JNK2 may lead to predominantly cytosolic responses (for example by binding to and phosphorylating and blocking the IRS proteins), while JNK3 will impact on nuclear responses (eg c-Jun expression or stability, transcriptional regulation of IRS2, etc). An important consequence of these recent works is that the JNK 1 and 2 probably mediate apoptosis mainly through cytosolic modifications of pre-existing proteins, while JNK3 appears to have a protective role which is essentially nuclear (transcriptionally) mediated.

These conclusions might help understanding why previous attempts at characterizing the transcriptional effectors of apoptosis regulated by JNK were often disappointing. In summary, we described here that expression of IRS2 is under the specific control of JNK3 in insulin-secreting cells. Hence, JNK3 appears to maintain the IRS2/Akt2 signaling module which is required to preserve beta-cell function Carfilzomib and mass. Microarray studies using islet cells lacking Jnk3 will establish the panel of genes that are regulated by JNK3 in pancreatic beta-cells (under investigation). Some of these genes might reveal new protective routes used by beta-cells to preserve their mass or function. Footnotes Competing Interests: The authors have declared that no competing interests exist. Funding: This study was supported by a grant from the Swiss National Foundation (FNS 320000-118193). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Beekeepers early identified the impact of bacterial organisms on honey bees, making pathological analyses and serological cultures important tools to assess hive diseases and oncoming threats [1].