Resumen de Regulation and actions mediated by C-jun N-terminal kinase pathaway
Jordi Lanuza Masdeu
As a part of the research-line that deals with physiological and pharmacological (anti-inflammatory and/or anti-diabetic) actions conducted by some nuclear receptor (NR) ligands through negative interference with the c-Jun N-terminal kinase (JNK) signaling pathway, this project is focused on studying the effects of the activation of JNK in a mouse model and evaluating the capacity of those ligands to recover the homeostasis. In parallel, there is a second project about the characterization of the crosstalk between the JNK pathway and NF-¿B, another major pathway in inflammation. The relevance of the activation of JNK in a wide range of pathologies with an inflammatory component, lead the group to the generation of a transgenic mouse carrying a a constitutively active form of the MAP2K of JNK, MKK7, with a conditional expression upon the regulation of the Cre recombinase. Despite these mice have no morphostructural affectation of the pancreatic islets or differences in the total insulin content, they have defective glucose homeostasis showing glucose intolerance and decreased insulin secretion in response to hyperglycemia. This reduction in glucose-induced insulin release is ß cell autonomous, as it is reproduced in isolated islets, and JNK activity dependent, as it is reverted by the specific inhibitor of JNK, TAT-JIPi. At molecular level, ß-cells with activated JNK have a blockage in the insulin-signaling pathway that reduces the secretion of insulin and the expression of insulin target genes. The treatment with rosiglitazone, an insulin-sensitizing drug of the thiazolidinedione family that inhibits JNK activation, restored insulin secretion in response to glucose in isolated islets and in vivo. All these data indicate that the activation of JNK is sufficient to promote central insulin resistance but is not sufficient to induce islet hyperplasia or ß-cell death. Moreover, these mice are protected from basal plasma hiperinsulinemia caused by aging or high fat diet challenge. Regarding the second project, the interaction between NF-¿B and JNK pathways, both signaling pathways are essential for the regulation of the immune and inflammatory response as well as other fundamental processes such as cell proliferation and survival. It was published that JNK was activating NF-¿B pathway by inducing the mRNA stabilization of the E3 ubiquitin ligase ¿TrcP. We have further reported that JNK is targeting the miRNA183/CRD-BP system to stabilize ßTrCP mRNA . At a protein level we have shown that SPK1-ßTrCP complex formation is required for JNK-dependent SKP1 and ßTrCP protein stabilization. Not only this but the ßTrCP substrate ß¿catenin is down regulated by the JNK-dependent increase of ßTrCP and the protein levels of SKP2 and its substrate p27 are oppositely regulated by JNK
