Phosphoinositide 3-kinase mediates protein kinase C beta II mRNA destabilization in rat A10 smooth muscle cell cultures exposed to high glucose.
High-glucose exposure down-regulates protein kinaseC beta II posttranscriptionally in rat and human vascular smooth muscle cells and contributes to increased cell proliferation. High-glucose-induced mRNA destabilization is specific for PKC beta II mRNA, while PKC beta I and other PKC mRNA are not affected. This study focused on whether glucose metabolism was required. The effect was blocked by cytochalasin B, suggesting a requirement for glucose uptake. Glucosamine did not mimic the effect, indicating that metabolism via hexosamine pathway was not involved. The effect was hexokinase-independent since 3-O-methylglucose, in a dose-dependent manner, mimicked high-glucose effects. Cycloheximide did not block the effect excluding dependency on new protein synthesis. Wortmannin and LY294002, phosphoinositide 3-kinase (PI3-kinase) inhibitors, blocked glucose effects in the presence of 5,6-dichloro-1-beta-d-ribofuranosylbenzimidazole. Glucose and 3-O-methylglucose activated PI3-kinase, and LY294002 blocked glucose effects on Akt phosphorylation. In these cells, high-glucose concentrations activated a metabolically linked signaling pathway independent of glucose metabolism to regulate mRNA processing.
Patel
Niketa A
NA
Department of Biochemistry, College of Medicine, University of South Florida, Tampa, USA.
Yamamoto
Mayumi
M
Illingworth
Philip
P
Mancu
Daniel
D
Mebert
Konrad
K
Chappell
David S
DS
Watson
James E
JE
Cooper
Denise R
DR
D000730:Androstadienes / Q000493:pharmacokinetics; D000818:Animals; D002455:Cell Division; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D003571:Cytochalasin B / Q000494:pharmacology; D004004:Dichlororibofuranosylbenzimidazole / Q000494:pharmacology; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005944:Glucosamine / Q000378:metabolism; D005947:Glucose / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D007527:Isoenzymes / Q000378:metabolism*; D009025:Morpholines / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism*; D064546:Protein Kinase C beta; D020871:RNA Stability; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D000077191:Wortmannin
D000730:Androstadienes; D002867:Chromones; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D009025:Morpholines; D012333:RNA, Messenger; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D003571:Cytochalasin B; D004004:Dichlororibofuranosylbenzimidazole; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D005947:Glucose; D005944:Glucosamine; D000077191:Wortmannin