title: Oxidative stress induces nucleo-cytoplasmic translocation of pancreatic transcription factor PDX-1 through activation of c-Jun NH(2)-terminal kinase.
abstract: Oxidative stress is induced in pancreatic beta-cells under diabetic conditions and causes beta-cell dysfunction. Antioxidant treatment of diabetic animals leads to recovery of insulin biosynthesis and increases the expression of its controlling transcription factor, pancreatic duodenal homeobox-1 (PDX-1), in pancreatic beta-cells. Here, we show that PDX-1 is translocated from the nuclei to the cytoplasm of pancreatic beta-cells in response to oxidative stress. When oxidative stress was charged upon beta-cell-derived HIT-T15 cells, both endogenous PDX-1 and exogenously introduced green fluorescent protein-tagged PDX-1 moved from the nuclei to the cytoplasm. The addition of a dominant negative form of c-Jun NH(2)-terminal kinase (JNK) inhibited oxidative stress-induced PDX-1 translocation, suggesting an essential role of JNK in mediating this phenomenon. Whereas the nuclear localization signal (NLS) in PDX-1 was not affected by oxidative stress, leptomycin B, a specific inhibitor of the classical leucine-rich nuclear export signal (NES), inhibited nucleo-cytoplasmic translocation of PDX-1 induced by oxidative stress. Moreover, we identified an NES at position 82-94 of the mouse PDX-1 protein. Thus, our present results revealed a novel mechanism that negatively regulates PDX-1 function. The identification of the NES, which overrides the function of the NLS in an oxidative stress-responsive, JNK-dependent manner, supports the complicated regulation of PDX-1 function in vivo and may further the understanding of beta-cell pathophysiology in diabetes.
authors.affiliation: Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Suita City, Osaka, Japan.
authors.forename: Dan
authors.initials: D
authors.lastname: Kawamori
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Kajimoto
authors.forename: Hideaki
authors.initials: H
authors.lastname: Kaneto
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Umayahara
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Fujitani
authors.forename: Takeshi
authors.initials: T
authors.lastname: Miyatsuka
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Watada
authors.forename: Ingo B
authors.initials: IB
authors.lastname: Leibiger
authors.forename: Yoshimitsu
authors.initials: Y
authors.lastname: Yamasaki
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Hori
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000502:physiology; D000818:Animals; D001692:Biological Transport / Q000502:physiology; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D003593:Cytoplasm / Q000378:metabolism*; D004789:Enzyme Activation / Q000502:physiology; D018398:Homeodomain Proteins; D007515:Islets of Langerhans / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases; D007930:Leucine; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D019913:Nuclear Localization Signals / Q000502:physiology; D018384:Oxidative Stress / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D015534:Trans-Activators / Q000378:metabolism*
chemical_list: D018398:Homeodomain Proteins; D019913:Nuclear Localization Signals; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D007930:Leucine