Involvement of protein kinase C beta 2 in c-myc induction by high glucose in pancreatic beta-cells.
The expression of the basic helix-loop-helix transcription factor c-Myc is induced in pancreatic islets of several different diabetic model animals and is possibly involved in suppression of the insulin gene transcription. In this study, we found that activity of protein kinase C is increased by high glucose, preceding the induction of c-myc expression and that PKC beta2 specifically regulates c-myc expression in pancreatic beta-cells. Since PKC alpha, beta2, delta, epsilon, and zeta were expressed in rat pancreatic islets, we prepared each wild type (WT) and dominant negative type (DN) PKC isoform (alpha, beta2, delta, epsilon, and zeta)-expressing adenovirus to examine the effect of each PKC isoform on c-myc expression. In isolated rat pancreatic islets, adenovirus-mediated overexpression of WT PKC beta2, but not other PKC isoforms, markedly increased c-myc expression. Moreover, c-myc induction by high glucose was suppressed by adenovirus-mediated overexpression of DN PKC beta2 but not by other DN PKC isoforms. Finally, adenovirus-mediated overexpression of WT PKC beta2, but not of other PKC isoforms, leads to suppression of the insulin gene transcription in pancreatic islets. These results suggest that at least some of the reduction of insulin gene transcription found in the diabetic state is mediated by PKC beta2 regulation of c-myc expression.
Kaneto
Hideaki
H
Section on Islet Transplantation and Cell Biology and Section on Vascular Cell Biology, Joslin Diabetes Center, Boston, Massachusetts 02215, USA. kaneto@osb.att.ne.jp
Suzuma
Kiyoshi
K
Sharma
Arun
A
Bonner-Weir
Susan
S
King
George L
GL
Weir
Gordon C
GC
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002478:Cells, Cultured; D004789:Enzyme Activation; D017930:Genes, Reporter; D016259:Genes, myc; D005947:Glucose / Q000494:pharmacology*; D007328:Insulin / Q000235:genetics; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D008297:Male; D016133:Polymerase Chain Reaction; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D064546:Protein Kinase C beta; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014158:Transcription, Genetic; D014162:Transfection
D007328:Insulin; D007527:Isoenzymes; D016271:Proto-Oncogene Proteins c-myc; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D005947:Glucose