Synthetic triterpenoids enhance transforming growth factor beta/Smad signaling.
Synthetic triterpenoids enhance transforming growth factor beta/Smad signaling.
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发表时间：
2003
期刊：
影响因子：
11.2
通讯作者：
N. Suh;A. Roberts;Stephanie Birkey Reffey;K. Miyazono;S. Itoh;P. ten Dijke;E. Heiss;A. Place;R. Risingsong;Charlotte R. Williams;T. Honda;G. Gribble;M. Sporn
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文献类型：
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作者：
N. Suh;A. Roberts;Stephanie Birkey Reffey;K. Miyazono;S. Itoh;P. ten Dijke;E. Heiss;A. Place;R. Risingsong;Charlotte R. Williams;T. Honda;G. Gribble;M. Sporn
我们研究了两种新合成的三萜类化合物2-氰基-3，12-二氧代齐墩果-1，9-二烯-28-酸（CDDO）及其衍生物1-（2-氰基-3，12-二氧代齐墩果-1，9-二烯-28-酰基）咪唑（CDDO-Im）对转化生长因子（TGF）-β/Smad信号转导的影响。这些药物在纳摩尔浓度下增加TGF-β依赖性基因的表达，例如纤溶酶原激活物抑制剂1和II型TGF-β受体的表达，并且它们在这方面与TGF-β协同作用。它们延长TGF-β诱导的Smad 2的活化，并显著增强Smad 3活化Smad结合元件CAGA-荧光素酶的能力。在转染试验中，它们逆转了Smad 7的抑制作用。CDDO和CDDO-Im还增强TGF-β超家族的另外两个成员（即激活素和骨形态发生蛋白）的途径中的Smad信号传导。最后，这些三萜类化合物诱导转录共激活因子p300-CBP相关因子的表达，并在这方面与TGF-β协同作用。这些是首次报道合成三萜类化合物增强Smad信号传导的研究，并应进一步优化其在预防或治疗TGF-β功能异常的疾病中的应用。
We have studied the effects of two new synthetic triterpenoids, 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) and its derivative, 1-(2-cyano-3,12-dioxooleana-1,9-dien-28-oyl) imidazole (CDDO-Im), on transforming growth factor (TGF)-beta/Smad signaling. These agents, at nanomolar concentrations, increase the expression of TGF-beta-dependent genes, such as those for plasminogen activator inhibitor 1 and the type II TGF-beta receptor, and they synergize with TGF-beta in this regard. They prolong the activation of Smad2 induced by TGF-beta and markedly enhance the ability of Smad3 to activate a Smad binding element, CAGA-luciferase. In transfection assays, they reverse the inhibitory effects of Smad7. CDDO and CDDO-Im also enhance Smad signaling in the pathways of two other members of the TGF-beta superfamily, namely, activin and bone morphogenetic protein. Finally, these triterpenoids induce expression of the transcriptional coactivator p300-CBP-associated factor and synergize with TGF-beta in this regard. These are the first studies to report enhancement of Smad signaling by synthetic triterpenoids and should further their optimal use for applications in prevention or treatment of diseases in which there is aberrant function of TGF-beta.