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首页> 外文期刊>American Journal of Physiology >Troglitazone acutely inhibits protein synthesis in endothelial cells via a novel mechanism involving protein phosphatase 2A-dependent p70 S6 kinase inhibition.
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Troglitazone acutely inhibits protein synthesis in endothelial cells via a novel mechanism involving protein phosphatase 2A-dependent p70 S6 kinase inhibition.

机译：曲格列酮通过涉及蛋白质磷酸酶2A依赖性p70 S6激酶抑制作用的新机制，急性抑制内皮细胞中的蛋白质合成。

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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.
机译：噻唑烷二酮（TZDs）是合成的过氧化物酶体增殖物激活的受体γ（PPARgamma）配体，与多种细胞中蛋白质合成的抑制作用有关，但其潜在机制仍然不清楚。我们报告，曲格列酮，第一种TZD药物，通过降低牛主动脉内皮细胞（BAEC）中的p70 S6激酶（p70S6K）活性来急性抑制蛋白质合成。这种抑制不伴随雷帕霉素（mTOR）哺乳动物靶标的磷酸化状态降低或体外激酶活性降低。此外，与雷帕霉素，一种特定的mTOR抑制剂和曲格列酮共同治疗可同时抑制p70S6K活性和蛋白质合成，这表明曲格列酮的抑制作用不受mTOR介导。野生型p70S6K基因的过表达显着逆转了曲格列酮诱导的蛋白合成抑制，表明p70S6K的重要作用。冈田酸是一种蛋白磷酸酶2A（PP2A）抑制剂，部分逆转了曲格列酮对p70S6K活性和蛋白合成的抑制作用。尽管曲格列酮不会改变总的细胞PP2A活性，但它增加了p70S6K和PP2A之间的物理缔合，表明了潜在的分子机制。 GW9662，一种PPARγ拮抗剂，没有改变任何观察到的抑制作用。最后，我们还发现，在BAEC和其他类型的内皮细胞中，曲格列酮对TZDs西格列酮，吡格列酮和罗格列酮的mTOR依赖性抑制机制均成立。总之，我们的数据首次证明了曲格列酮（也许还有其他TZD）通过独立于mTOR和PPARgamma的PP2A依赖性机制急剧降低了p70S6K活性，从而导致内皮细胞中蛋白质合成受到抑制。

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