Transcriptional repression of IKKβ by p53 in arsenite-induced GADD45α accumulation and apoptosis.
Transcriptional repression of IKKβ by p53 in arsenite-induced GADD45α accumulation and apoptosis.
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p53 在亚砷酸盐诱导的 GADD45 α 积累和细胞凋亡中对 IKK β 的转录抑制
DOI：
10.1038/s41388-018-0478-7
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发表时间：
2019-01
期刊：
影响因子：
8
通讯作者：
Song L
中科院分区：
文献类型：
--
作者：
Hu Y;Jin R;Gao M;Xu H;Zou S;Li X;Xing C;Wang Q;Wang H;Feng J;Hu M;Song L
我们之前的研究表明，GADD45α是一种易感蛋白，在静止的HepG2肝癌细胞中经历mdm2依赖性的组成型泛素化和降解。亚砷酸盐暴露诱导核糖体蛋白S7介导的核糖体应激反应，可阻断MDM2活性，导致GADD45α积累和细胞凋亡。在本研究中，我们发现IKK的催化亚基之一IKKβ在稳定MDM2中发挥了一种新的IKKα和NF-κ b无关的功能，因此有助于静止HepG2细胞中GADD45α的泛素化降解。亚砷酸盐刺激诱导p53反激活，与下游靶点Ets-1形成复合体，进而协同抑制IKKβ转录，降低MDM2稳定性，最终消除MDM2对GADD45α诱导的抑制作用。此外，DAPK1作为上游蛋白激酶，可触发p53/ ets -1依赖性IKKβ和MDM2的减少以及GADD45α的积累，从而促进HepG2细胞的凋亡。随后的研究进一步发现，在亚砷酸盐等肿瘤治疗剂诱导的多种癌细胞凋亡过程中，DAPK1/p53/Ets-1/IKKβ/MDM2/GADD45α级联的激活是一个共同的信号事件。因此，我们得出结论，本研究的数据揭示了IKKβ在负调控GADD45α蛋白稳定性中的新作用，以及p53依赖性IKKβ减少在介导癌细胞凋亡中的作用。
Our previous studies revealed that GADD45α is a liable protein, which undergoes MDM2-dependent constitutive ubiquitination and degradation in resting HepG2 hepatoma cells. Arsenite exposure induces ribosomal stress responses mediated by the ribosomal protein S7, which can block MDM2 activity and result in GADD45α accumulation and cell apoptosis. In the present study, we found that one of the catalytic subunits of IκB kinase (IKK), IKKβ, exerted a novel IKKα- and NF-κB-independent function in stabilizing MDM2 and therefore contributed to ubiquitination-dependent degradation of GADD45α in resting HepG2 cells. Arsenite stimulation induced transactivation of p53, which formed a complex with its downstream target, Ets-1, and then synergistically repressed IKKβ transcription, reduced MDM2 stability, and ultimately removed the inhibitory effect of MDM2 on GADD45α induction. In addition, DAPK1 functioned as an upstream protein kinase triggering p53/Ets-1-dependent IKKβ and MDM2 reduction and GADD45α accumulation, thus promoting apoptosis in HepG2 cells. Subsequent studies further revealed that the activation of the DAPK1/p53/Ets-1/IKKβ/MDM2/GADD45α cascade was a common signaling event in mediating apoptosis of diverse cancer cells induced by arsenite and other tumor therapeutic agents. Therefore, we conclude that data in the current study have revealed a novel role for IKKβ in negatively regulating GADD45α protein stability and the contribution of p53-dependent IKKβ reduction to mediating cancer cell apoptosis.
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GADD45蛋白质：与衰老，寿命和与年龄相关的病理相关。
影响因子：
13.1
作者：
Moskalev, Alexey A.;Smit-McBride, Zeljka;Shaposhnikov, Mikhail V.;Plyusnina, Ekaterina N.;Zhavoronkov, Alex;Budovsky, Arie;Tacutu, Robi;Fraifeld, Vadim E.
通讯作者：
Fraifeld, Vadim E.
影响因子：
4.3
作者：
Li, Yi;Hao, Yi;Song, Lun
通讯作者：
Song, Lun
影响因子：
4.8
作者：
Pastorcic, M;Das, HK
通讯作者：
Das, HK
影响因子：
8
作者：
Fischer M
通讯作者：
Fischer M
影响因子：
4.8
作者：
Li, BQ;Lee, MYW
通讯作者：
Lee, MYW