Troglitazone acutely inhibits protein synthesis in endothelial cells via a novel mechanism involving protein phosphatase 2A-dependent p70 S6 kinase inhibition
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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DOI：
10.1152/ajpcell.00491.2005
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发表时间：
2006-08-01
影响因子：
5.5
通讯作者：
Jo, Inho
中科院分区：
文献类型：
--
作者：
Cho, Du-Hyong;Choi, Yoon Jung;Jo, Inho
曲格列酮通过一种涉及蛋白磷酸酶2a依赖性p70 S6激酶抑制的新机制急性抑制内皮细胞的蛋白质合成。[J]中国生物医学工程学报，2006；doi: 10.1152 / ajpcell.00491.2005。Thiazolidinediones （TZDs）是一种合成过氧化物酶体增殖体激活受体γ (PPAR γ)配体，已被认为与多种细胞中蛋白质合成的抑制有关，但其潜在机制尚不清楚。我们报道了曲格列酮，第一种TZD药物，通过降低牛主动脉内皮细胞（BAEC）的p70s6激酶（p70S6K）活性来急性抑制蛋白质合成。这种抑制并不伴随着雷帕霉素靶蛋白（mTOR）磷酸化状态或体外激酶活性的降低。此外，与雷帕霉素（一种特异性mTOR抑制剂）和曲格列酮共同治疗可抑制p70S6K活性和蛋白质合成，表明曲格列酮的抑制作用不是由mTOR介导的。野生型p70S6K基因的过表达显著逆转了曲格列酮诱导的蛋白合成抑制，表明p70S6K在其中发挥了重要作用。蛋白磷酸酶2A （PP2A）抑制剂Okadaic acid部分逆转了曲格列酮诱导的p70S6K活性和蛋白合成的抑制。虽然曲格列酮没有改变细胞总PP2A活性，但它增加了p70S6K和PP2A之间的物理关联，提示潜在的分子机制。GW9662，一种PPAR γ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抑制机制与mtor无关。总之，我们的数据首次证明，曲格列酮（可能还有其他TZDs）通过一种不依赖于mTOR和PPAR γ的pp2a依赖性机制急剧降低p70S6K活性，从而抑制内皮细胞中的蛋白质合成。
Troglitazone acutely inhibits protein synthesis in endothelial cells via a novel mechanism involving protein phosphatase 2A-dependent p70 S6 kinase inhibition. Am J Physiol Cell Physiol 291: C317-C326, 2006; doi:10.1152/ajpcell.00491.2005. - Thiazolidinediones (TZDs), synthetic peroxisome proliferator-activated receptor gamma (PPAR gamma) 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 PPAR gamma 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 PPAR gamma, leading to the inhibition of protein synthesis in endothelial cells.