Yoon Kwiyeom, Jung Eun Joo, Lee Soo Young
Division of Life and Pharmaceutical Sciences, Center for Cell Signaling & Drug Discovery Research, Ewha Womans University, 11-1, Daehyun-dong, Seoul 120-750, Republic of Korea.
Biochem Biophys Res Commun. 2008 Jun 20;371(1):118-21. doi: 10.1016/j.bbrc.2008.04.007. Epub 2008 Apr 11.
We recently demonstrated that the tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) helps maintenance of cell survival by regulating glycogen synthase kinase 3beta (GSK3beta) activity during TNF signaling. However, the molecular linkage between TRAF6 and GSK3beta signaling is unknown. Herein, we showed that TRAF6 positively regulated cell survival by modulating PI3K-Akt-GSK3beta cascades. In 3T3 cells lacking TRAF6, but not those lacking TRAF2, TNF stimulation led to prolonged hyperphosphorylation of Akt, which coincided with the activation of upstream PI3K. Pharmacologically blocking PI3K significantly inhibited Akt and GSK3beta phosphorylation. Importantly, PI3K inhibition rescued cell death in TRAF6-null 3T3 cells. These data suggested TRAF6 regulates TNF-mediated cell survival through PI3K-Akt-GSK3beta cascades.
我们最近证明，肿瘤坏死因子（TNF）受体相关因子6（TRAF6）在TNF信号传导过程中通过调节糖原合酶激酶3β（GSK3β）活性来帮助维持细胞存活。然而，TRAF6与GSK3β信号传导之间的分子联系尚不清楚。在此，我们表明TRAF6通过调节PI3K-Akt-GSK3β级联反应来正向调节细胞存活。在缺乏TRAF6的3T3细胞中，而非缺乏TRAF2的细胞中，TNF刺激导致Akt的持续过度磷酸化，这与上游PI3K的激活相一致。药理学上阻断PI3K可显著抑制Akt和GSK3β的磷酸化。重要的是，PI3K抑制可挽救TRAF6基因敲除的3T3细胞中的细胞死亡。这些数据表明TRAF6通过PI3K-Akt-GSK3β级联反应调节TNF介导的细胞存活。
