Involvement of c-Jun N-terminal kinase in oxidative stress-mediated suppression of insulin gene expression.
Oxidative stress, which is found in pancreatic beta-cells in the diabetic state, suppresses insulin gene transcription and secretion, but the signaling pathways involved in the beta-cell dysfunction induced by oxidative stress remain unknown. In this study, subjecting rat islets to oxidative stress activates JNK, p38 MAPK, and protein kinase C, preceding the decrease of insulin gene expression. Adenovirus-mediated overexpression of dominant-negative type (DN) JNK, but not the p38 MAPK inhibitor SB203580 nor the protein kinase C inhibitor GF109203X, protected insulin gene expression and secretion from oxidative stress. Moreover, wild type JNK overexpression suppressed both insulin gene expression and secretion. These results were correlated with changes in the binding of the important transcription factor PDX-1 to the insulin promoter; adenoviral overexpression of DN-JNK preserved PDX-1 DNA binding activity in the face of oxidative stress, whereas wild type JNK overexpression decreased PDX-1 DNA binding activity. Furthermore, to examine whether suppression of the JNK pathway can protect beta-cells from the toxic effects of hyperglycemia, rat islets were infected with DN-JNK expressing adenovirus or control adenovirus and transplanted under renal capsules of streptozotocin-induced diabetic nude mice. In mice receiving DN-JNK overexpressing islets, insulin gene expression in islet grafts was preserved, and hyperglycemia was ameliorated compared with control mice. In conclusion, activation of JNK is involved in the reduction of insulin gene expression by oxidative stress, and suppression of the JNK pathway protects beta-cells from oxidative stress.
Kaneto
Hideaki
H
Section on Islet Transplantation and Cell Biology, Joslin Diabetes Center, Boston, Massachusetts 02215, USA.
Xu
Gang
G
Fujii
Nobuharu
N
Kim
Shokei
S
Bonner-Weir
Susan
S
Weir
Gordon C
GC
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D004789:Enzyme Activation; D005786:Gene Expression Regulation / Q000502:physiology*; D007328:Insulin / Q000235:genetics*; D007515:Islets of Langerhans / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases; D008297:Male; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000502:physiology*; D018384:Oxidative Stress; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D048051:p38 Mitogen-Activated Protein Kinases
D017931:DNA Primers; D007328:Insulin; D011493:Protein Kinase C; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases