Ferroptosis as a p53-mediated activity during tumour suppression.
Ferroptosis as a p53-mediated activity during tumour suppression.
复制标题
DOI：
10.1038/nature14344
复制
发表时间：
2015-04-02
期刊：
影响因子：
64.8
通讯作者：
Gu, Wei
中科院分区：
文献类型：
--
作者：
Jiang, Le;Kon, Ning;Li, Tongyuan;Wang, Shang-Jui;Su, Tao;Hibshoosh, Hanina;Baer, Richard;Gu, Wei
尽管p53介导的细胞周期阻滞、衰老和凋亡是癌症发展的关键障碍，但新的证据表明p53的代谢活动也很重要。在这里，我们发现p53通过抑制SLC7A11（胱氨酸/谷氨酸反转运蛋白的关键成分）的表达，抑制胱氨酸摄取并使细胞对铁死亡（一种非凋亡形式的细胞死亡）敏感。值得注意的是，p533KR是一种乙酰化缺陷突变体，不能诱导细胞周期阻滞、衰老和凋亡，但在活性氧（ROS）诱导的应激下，它完全保留了调节SLC7A11表达和诱导铁死亡的能力。对突变小鼠的分析表明，这些非规范p53活性有助于胚胎发育和Mdm2缺失相关的致死率。此外，SLC7A11在人类肿瘤中高表达，其过表达抑制ros诱导的铁下垂，并在异种移植物模型中消除p533kr介导的肿瘤生长抑制。我们的发现揭示了一种基于p53调节胱氨酸代谢、ROS反应和铁下垂的肿瘤抑制新模式。
Although p53–mediated cell–cycle arrest, senescence and apoptosis serve as critical barriers to cancer development, emerging evidence suggests that the metabolic activities of p53 are also important. Here we show that p53 inhibits cystine uptake and sensitizes cells to ferroptosis, a non–apoptotic form of cell death, by repressing expression of SLC7A11, a key component of the cystine/glutamate antiporter. Notably, p533KR, an acetylation–defective mutant that fails to induce cell–cycle arrest, senescence and apoptosis, fully retains the ability to regulate SLC7A11 expression and induce ferroptosis upon reactive oxygen species (ROS)–induced stress. Analysis of mutant mice shows that these non–canonical p53 activities contribute to embryonic development and the lethality associated with loss of Mdm2. Moreover, SLC7A11 is highly expressed in human tumours, and its overexpression inhibits ROS–induced ferroptosis and abrogates p533KR–mediated tumour growth suppression in xenograft models. Our findings uncover a new mode of tumour suppression based on p53 regulation of cystine metabolism, ROS responses and ferroptosis.
登录
查看更多内容
影响因子：
4
作者：
Aylon, Yael;Oren, Moshe
通讯作者：
Oren, Moshe
影响因子：
64.5
作者：
Dixon SJ;Lemberg KM;Lamprecht MR;Skouta R;Zaitsev EM;Gleason CE;Patel DN;Bauer AJ;Cantley AM;Yang WS;Morrison B 3rd;Stockwell BR
通讯作者：
Stockwell BR
影响因子：
50.3
作者：
Lu, Min;Breyssens, Hilde;Lu, Xin
通讯作者：
Lu, Xin
影响因子：
8
作者：
Kon, N.;Kobayashi, Y.;Li, M.;Brooks, C. L.;Ludwig, T.;Gu, W.
通讯作者：
Gu, W.
影响因子：
5.3
作者：
Mendrysa, SM;McElwee, MK;Perry, ME
通讯作者：
Perry, ME