ROS-dependent activation of JNK converts p53 into an efficient inhibitor of oncogenes leading to robust apoptosis.
ROS-dependent activation of JNK converts p53 into an efficient inhibitor of oncogenes leading to robust apoptosis.
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DOI：
10.1038/cdd.2013.186
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发表时间：
2014-04
影响因子：
12.4
通讯作者：
中科院分区：
文献类型：
--
作者：
挽救P53抑癌基因是一种很有吸引力的癌症治疗方法。然而，药物激活的p53可以诱导从细胞死亡到生长停滞和DNA修复的多种反应，这限制了P53再激活药物在临床上的有效应用。阐明决定P53激活的生物学结果的分子机制仍然是P53领域的一个巨大挑战。在此，我们报告了P53的药理激活和硫氧还蛋白还原酶的抑制以及活性氧自由基(ROS)的产生，导致了癌细胞的合成杀伤力。ROS促进c-jun氨基末端激酶(JNK)的激活和DNA损伤反应，与P53建立正反馈回路。这将P53诱导的生长停滞/衰老转化为细胞凋亡。我们鉴定了几个被P53以JNK依赖的方式抑制的生存癌基因，包括MCL1，PI3K，eIF4E，以及P53抑制剂Wip1和MDMX。此外，我们发现Wip1是JNK下游的关键执行者之一，其消融可以增强和持续的P53转录反应，从而导致细胞死亡。我们的研究为以受控方式操纵P53反应提供了新的见解。此外，我们的结果可能使新的药理学策略能够利用异常高的ROS水平，通常与癌症中更高的侵袭性有关，在药物重新激活P53时选择性地杀死癌细胞。
Rescue of the p53 tumor suppressor is an attractive cancer therapy approach. However, pharmacologically activated p53 can induce diverse responses ranging from cell death to growth arrest and DNA repair, which limits the efficient application of p53-reactivating drugs in clinic. Elucidation of the molecular mechanisms defining the biological outcome upon p53 activation remains a grand challenge in the p53 field. Here, we report that concurrent pharmacological activation of p53 and inhibition of thioredoxin reductase followed by generation of reactive oxygen species (ROS), result in the synthetic lethality in cancer cells. ROS promote the activation of c-Jun N-terminal kinase (JNK) and DNA damage response, which establishes a positive feedback loop with p53. This converts the p53-induced growth arrest/senescence to apoptosis. We identified several survival oncogenes inhibited by p53 in JNK-dependent manner, including Mcl1, PI3K, eIF4E, as well as p53 inhibitors Wip1 and MdmX. Further, we show that Wip1 is one of the crucial executors downstream of JNK whose ablation confers the enhanced and sustained p53 transcriptional response contributing to cell death. Our study provides novel insights for manipulating p53 response in a controlled way. Further, our results may enable new pharmacological strategy to exploit abnormally high ROS level, often linked with higher aggressiveness in cancer, to selectively kill cancer cells upon pharmacological reactivation of p53.
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影响因子：
3.7
作者：
Anestål K;Prast-Nielsen S;Cenas N;Arnér ES
通讯作者：
Arnér ES
影响因子：
64.8
作者：
Bartkova, J;Horejsi, Z;Bartek, J
通讯作者：
Bartek, J
影响因子：
50.3
作者：
Jackson JG;Pant V;Li Q;Chang LL;Quintás-Cardama A;Garza D;Tavana O;Yang P;Manshouri T;Li Y;El-Naggar AK;Lozano G
通讯作者：
Lozano G
DOI：
10.1016/j.bbrc.2010.09.053
发表时间：
2010-10-22
影响因子：
3.1
作者：
He, Xu;Andersson, Goran;Li, Yan
通讯作者：
Li, Yan
影响因子：
4
作者：
Marine, Jean-Christophe W.;Dyer, Michael A.;Jochemsen, Aart G.
通讯作者：
Jochemsen, Aart G.