Troglitazone acutely inhibits protein synthesis in endothelial cells via a novel mechanism involving protein phosphatase 2A-dependent p70 S6 kinase inhibition.
Thiazolidinediones (TZDs), synthetic peroxisome proliferator-activated receptor gamma (PPARgamma) ligands, have been implicated in the inhibition of protein synthesis in a variety of cells, but the underlying mechanisms remain obscure. We report that troglitazone, the first TZD drug, acutely inhibited protein synthesis by decreasing p70 S6 kinase (p70S6K) activity in bovine aortic endothelial cells (BAEC). This inhibition was not accompanied by decreased phosphorylation status or in vitro kinase activity of mammalian target of rapamycin (mTOR). Furthermore, cotreatment with rapamycin, a specific mTOR inhibitor, and troglitazone additively inhibited both p70S6K activity and protein synthesis, suggesting that the inhibitory effects of troglitazone are not mediated by mTOR. Overexpression of the wild-type p70S6K gene significantly reversed the troglitazone-induced inhibition of protein synthesis, indicating an important role of p70S6K. Okadaic acid, a protein phosphatase 2A (PP2A) inhibitor, partially reversed the troglitazone-induced inhibition of p70S6K activity and protein synthesis. Although troglitazone did not alter total cellular PP2A activity, it increased the physical association between p70S6K and PP2A, suggesting an underlying molecular mechanism. GW9662, a PPARgamma antagonist, did not alter any of the observed inhibitory effects. Finally, we also found that the mTOR-independent inhibitory mechanism of troglitazone holds for the TZDs ciglitazone, pioglitazone, and rosiglitazone, in BAEC and other types of endothelial cells tested. In conclusion, our data demonstrate for the first time that troglitazone (and perhaps other TZDs) acutely decreases p70S6K activity through a PP2A-dependent mechanism that is independent of mTOR and PPARgamma, leading to the inhibition of protein synthesis in endothelial cells.
Cho
Du-Hyong
DH
Dept. of Biomedical Sciences, National Institute of Health, 5 Nokbun-dong, Eunpyunggu, Seoul 122-701, Korea.
Choi
Yoon Jung
YJ
Jo
Sangmee Ahn
SA
Ryou
Jungsang
J
Kim
Jin Yi
JY
Chung
Jongkyeong
J
Jo
Inho
I
D000818:Animals; D002417:Cattle; D002478:Cells, Cultured; D002839:Chromans / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology*; D004789:Enzyme Activation / Q000187:drug effects; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism*; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014176:Protein Biosynthesis / Q000187:drug effects / Q000502:physiology*; D054648:Protein Phosphatase 2; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000037:antagonists & inhibitors / Q000378:metabolism*; D045162:Thiazolidinediones / Q000008:administration & dosage*; D000077288:Troglitazone
D002839:Chromans; D047495:PPAR gamma; D045162:Thiazolidinediones; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2; D000077288:Troglitazone