Forkhead box O1/pancreatic and duodenal homeobox 1 intracellular translocation is regulated by c-Jun N-terminal kinase and involved in prostaglandin E2-induced pancreatic β-cell dysfunction

Abstract

Prostaglandin E2 (PGE2) is a well-known mediator of β-cell dysfunction in both type 1 and type 2 diabetes. We recently reported that down-regulation of the Akt pathway activity is implicated in PGE 2-induced pancreatic β-cell dysfunction. The aim of this study was to further dissect the signaling pathway of this process in pancreatic β-cell line HIT-T15 cells and primary mouse islets. We found that PGE 2 time-dependently increased the c-Jun N-terminal kinase (JNK) pathway activity. JNK inhibition by the JNK-specific inhibitor SP600125 reversed PGE2-inhibited glucose-stimulated insulin secretion (GSIS). PGE 2 induced dephosphorylation of Akt and FOXO1, leading to nuclear localization and transactivation of FOXO1. Activation of FOXO1 induced nuclear exclusion but had no obvious effect onthe whole-cell protein level of pancreatic and duodenal homeobox 1 (PDX1). However, these effects were all attenuated by JNK inhibition. Furthermore, adenovirus-mediated overexpression of dominant-negative (DN)-FOXO1 abolished whereas constitutively active (CA)-FOXO1 mimicked the effects of PGE2 on GSIS in isolated mouse islets. In addition, we demonstrated that DN-JNK1 but not DN-JNK2 or CA-Akt abolished the PGE2-induced AP-1 luciferase reporter activity, whereas DN-JNK1 and CA-Akt but not DN-JNK2 reversed the effect of PGE2 on FOXO1 transcriptional activity, and overexpression of DN-JNK1 rescued PGE 2-impaired GSIS in mouse islets. Our results revealed that activation of the JNK is involved in PGE2-induced β-cell dysfunction. PGE2-mediated JNK1 activation, through dephosphorylation of Akt and FOXO1, leads to nuclear accumulation of FOXO1 and nucleocytoplasmic shuttling of PDX1, finally resulting in defective GSIS in pancreatic β-cells. Copyright © 2009 by The Endocrine Society.