The role of phospholipase D in modulating the MTOR signaling pathway in polycystic kidney disease.
The role of phospholipase D in modulating the MTOR signaling pathway in polycystic kidney disease.
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DOI：
10.1371/journal.pone.0073173
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Serra AL
中科院分区：
文献类型：
--
作者：
Liu Y;Käch A;Ziegler U;Ong AC;Wallace DP;Arcaro A;Serra AL
哺乳动物雷帕霉素靶蛋白（mTOR）信号通路在多囊肾病（PKD）中异常激活。新出现的证据表明磷脂酶D（PLD）及其产物磷脂酸（PA）调节mTOR活性。在这项研究中，我们在体外评估PLD和PA对PKD中mTOR信号通路的调节功能。我们发现在PKD细胞中PLD活性的基础水平升高。针对PLD的小分子抑制剂抑制PKD细胞增殖并阻断mTOR信号，而外源性PA刺激mTOR信号并消除PLD对PKD细胞增殖的抑制作用。我们还表明，阻断PLD活性增强了PKD细胞对雷帕霉素的敏感性，PLD抑制剂和雷帕霉素的组合协同抑制PKD细胞增殖。此外，我们证明靶向mTOR不诱导自噬，而靶向PLD诱导自噬体形成。综上所述，我们的研究结果表明，在PKD细胞中，mTOR通路激活失调部分由PLD信号传导增加介导。用药理学抑制剂靶向PLD亚型可能代表PKD的新治疗策略。
The mammalian target of rapamycin (mTOR) signaling pathway is aberrantly activated in polycystic kidney disease (PKD). Emerging evidence suggests that phospholipase D (PLD) and its product phosphatidic acid (PA) regulate mTOR activity. In this study, we assessed in vitro the regulatory function of PLD and PA on the mTOR signaling pathway in PKD. We found that the basal level of PLD activity was elevated in PKD cells. Targeting PLD by small molecule inhibitors reduced cell proliferation and blocked mTOR signaling, whereas exogenous PA stimulated mTOR signaling and abolished the inhibitory effect of PLD on PKD cell proliferation. We also show that blocking PLD activity enhanced the sensitivity of PKD cells to rapamycin and that combining PLD inhibitors and rapamycin synergistically inhibited PKD cell proliferation. Furthermore, we demonstrate that targeting mTOR did not induce autophagy, whereas targeting PLD induced autophagosome formation. Taken together, our findings suggest that deregulated mTOR pathway activation is mediated partly by increased PLD signaling in PKD cells. Targeting PLD isoforms with pharmacological inhibitors may represent a new therapeutic strategy in PKD.
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影响因子：
4.8
作者：
Lehman, Nicholas;Ledford, Bill;Gomez-Cambronero, Julian
通讯作者：
Gomez-Cambronero, Julian
DOI：
10.1158/1078-0432.ccr-08-0102
发表时间：
2008-07-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Garcia A;Zheng Y;Zhao C;Toschi A;Fan J;Shraibman N;Brown HA;Bar-Sagi D;Foster DA;Arbiser JL
通讯作者：
Arbiser JL
影响因子：
56.9
作者：
Fang, YM;Vilella-Bach, M;Chen, J
通讯作者：
Chen, J
影响因子：
13.3
作者：
Dalby KN;Tekedereli I;Lopez-Berestein G;Ozpolat B
通讯作者：
Ozpolat B
DOI：
10.1083/jcb.201006173
发表时间：
2010-11-15
期刊：
The Journal of cell biology
影响因子：
--
作者：
Chapin HC;Caplan MJ
通讯作者：
Caplan MJ