Proteomic analysis shows synthetic oleanane triterpenoid binds to mTOR.
Proteomic analysis shows synthetic oleanane triterpenoid binds to mTOR.
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DOI：
10.1371/journal.pone.0022862
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Liby KT
中科院分区：
文献类型：
--
作者：
Yore MM;Kettenbach AN;Sporn MB;Gerber SA;Liby KT
针对多种疾病相关网络的新型多功能药物为许多疾病的预防和治疗提供了一种新的方法。新合成的齐墩果烷三萜(SO)类化合物，如CDDO(2-氰基-3，12-二氧代油酸-1，9-二烯-28-OIC酸)及其衍生物，是最初用于预防和治疗炎症和氧化应激的多功能化合物。然而，这些SO的蛋白结合伙伴和作用机制还没有完全了解。在这里，我们通过结合亲和纯化和质谱学蛋白质组学分析来鉴定整个细胞中的577个候选结合蛋白，从而表征了一种SO的假定靶标CDDO-咪唑(CDDO-Im)。这个SO药物相互作用组由一组不同但相互关联的信号网络组成；对蛋白质相互作用组的生物信息学分析确定了SO靶向的典型信号通路，包括视黄酸受体(RAR)、雌激素受体(ER)、胰岛素受体(IR)、Janus激酶/信号转导和转录激活因子(JAK/STAT)以及磷酸酶和紧张素同源物(PTEN)。然后，下拉研究进一步验证了假定目标的子集。此外，我们现在首次证明了雷帕霉素的哺乳动物靶点(MTOR)是CDDO-Im的直接靶点。我们还表明，CDDO-Im通过与mTOR结合并抑制其激酶活性来阻断胰岛素诱导的这一途径的激活。我们的基础研究证实，SO，CDDO-Im，作用于蛋白质网络，诱导其药理活性。
New multifunctional drugs that target multiple disease-relevant networks offer a novel approach to the prevention and treatment of many diseases. New synthetic oleanane triterpenoids (SO), such as CDDO (2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid) and its derivatives, are multifunctional compounds originally developed for the prevention and treatment of inflammation and oxidative stress. However, the protein binding partners and mechanisms of action of these SO are not yet fully understood. Here we characterize the putative target profile of one SO, CDDO-Imidazolide (CDDO-Im), by combining affinity purification with mass spectroscopic proteomic analysis to identify 577 candidate binding proteins in whole cells. This SO pharmaco-interactome consists of a diverse but interconnected set of signaling networks; bioinformatic analysis of the protein interactome identified canonical signaling pathways targeted by the SO, including retinoic acid receptor (RAR), estrogen receptor (ER), insulin receptor (IR), janus kinase/signal transducers and activators of transcription (JAK/STAT), and phosphatase and tensin homolog (PTEN). Pull-down studies then further validated a subset of the putative targets. In addition, we now show for the first time that the mammalian target of rapamycin (mTOR) is a direct target of CDDO-Im. We also show that CDDO-Im blocks insulin-induced activation of this pathway by binding to mTOR and inhibiting its kinase activity. Our basic studies confirm that the SO, CDDO-Im, acts on a protein network to elicit its pharmacological activity.
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影响因子：
14.9
作者：
Jensen LJ;Kuhn M;Stark M;Chaffron S;Creevey C;Muller J;Doerks T;Julien P;Roth A;Simonovic M;Bork P;von Mering C
通讯作者：
von Mering C
影响因子：
2.7
作者：
Honda, T;Rounds, BV;Sporn, MB
通讯作者：
Sporn, MB
影响因子：
6.8
作者：
Hopkins, AL;Mason, JS;Overington, JP
通讯作者：
Overington, JP
DOI：
10.1073/pnas.0500815102
发表时间：
2005-03-22
影响因子：
11.1
作者：
Dinkova-Kostova, AT;Liby, KT;Talalay, P
通讯作者：
Talalay, P
影响因子：
1.8
作者：
Cano, Marisol;Thimmalappula, Rajesh;Fujihara, Masashi;Nagai, Norihiro;Sporn, Michael;Wang, Ai Ling;Neufeld, Arthur H.;Biswal, Shyam;Handa, James T.
通讯作者：
Handa, James T.