The transcription-independent mitochondrial p53 program is a major contributor to nutlin-induced apoptosis in tumor cells.
The transcription-independent mitochondrial p53 program is a major contributor to nutlin-induced apoptosis in tumor cells.
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DOI：
10.4161/cc.8.11.8596
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发表时间：
2009-06-01
期刊：
影响因子：
--
通讯作者：
Moll UM
中科院分区：
文献类型：
--
作者：
Vaseva AV;Marchenko ND;Moll UM
在保留野生型 p53 的肿瘤中诱导 p53 激活的策略对于癌症治疗来说是有希望的。 Nutlin 是一种有效的选择性药理学 MDM2 抑制剂，可竞争性地与其 p53 结合袋结合，从而导致非遗传毒性的 p53 稳定并激活生长停滞和凋亡途径。 Nutlin 诱导的细胞凋亡被认为是通过 p53 的转录程序发生的。在这里，我们报道转录独立的线粒体 p53 程序在 Nutlin 诱导的 p53 介导的肿瘤细胞死亡中发挥重要作用。除了核稳定性外，Nutlin 还会导致细胞质 p53 积累并易位至线粒体。单泛素化 p53 源自独特的细胞质池，是响应应激而易位至线粒体的首选 p53 物种。 Nutlin 不会干扰 MDM2 单泛素化 p53 的能力，因为 MDM2-p53 复合物仅部分被破坏，并且 Nutlin 稳定的 MDM2 保留了其 E3 泛素连接酶活性。 Nutlin 诱导的线粒体 p53 易位是快速的，并且与诱导 p53 靶基因之前的细胞色素 C 释放相关。 Pifithrin μ 对线粒体 p53 易位的特异性抑制使凋亡 Nutlin 反应降低了 2.5 倍，强调了 p53 线粒体程序在 Nutlin 诱导的细胞凋亡中的重要性。令人惊讶的是，通过 α-鹅膏菌素或 p53 特异性转录抑制剂 Pifithrin α 阻断 p53 的转录臂，不仅不能抑制，而且会大大增强 Nutlin 诱导的细胞凋亡。总之，直接线粒体程序是 Nutlin 诱导 p53 介导的细胞凋亡的主要机制。此外，至少在某些肿瘤中，处于净平衡状态的转录p53活性不仅对于凋亡Nutlin反应是可有可无的，而且似乎积极阻断其治疗效果。
Strategies to induce p53 activation in tumors that retain wild-type p53 are promising for cancer therapy. Nutlin is a potent and selective pharmacological MDM2 inhibitor that competitively binds to its p53-binding pocket, thereby leading to non-genotoxic p53 stabilization and activation of growth arrest and apoptosis pathways. Nutlin-induced apoptosis is thought to occur via p53’s transcriptional program. Here we report that the transcription-independent mitochondrial p53 program plays an important role in Nutlin-induced p53-mediated tumor cell death. Aside from nuclear stabilization, Nutlin causes cytoplasmic p53 accumulation and translocation to mitochondria. Monoubiquitinated p53, originating from a distinct cytoplasmic pool, is the preferred p53 species that translocates to mitochondria in response to stress. Nutlin does not interfere with MDM2’s ability to monoubiquitinate p53, due to the fact that MDM2-p53 complexes are only partially disrupted and that Nutlin-stabilized MDM2 retains its E3 ubiquitin ligase activity. Nutlin-induced mitochondrial p53 translocation is rapid and associated with cytochrome C release that precedes induction of p53 target genes. Specific inhibition of mitochondrial p53 translocation by Pifithrin μ reduces the apoptotic Nutlin response by 2.5-fold, underlining the significance of p53’s mitochondrial program in Nutlin-induced apoptosis. Surprisingly, blocking the transcriptional arm of p53, either via α-Amanitin or the p53-specific transcriptional inhibitor Pifithrin α, not only fails to inhibit, but greatly potentiates Nutlin-induced apoptosis. In sum, the direct mitochondrial program is a major mechanism in Nutlin-induced p53-mediated apoptosis. Moreover, at least in some tumors the transcriptional p53 activities in net balance not only are dispensable for the apoptotic Nutlin response, but appear to actively block its therapeutic effect.
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DOI：
10.1158/1078-0432.ccr-07-5136
发表时间：
2008-09-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Shangary S;Wang S
通讯作者：
Wang S
影响因子：
20.3
作者：
Secchiero, Paola;Barbarotto, Elisa;Zauli, Giorgio
通讯作者：
Zauli, Giorgio
DOI：
10.1152/ajpheart.00759.2003
发表时间：
2004-03-01
影响因子：
4.8
作者：
Liu, XW;Chua, C;Chua, BHL
通讯作者：
Chua, BHL
影响因子：
4.8
作者：
Friedler, A;Veprintsev, DB;Fersht, AR
通讯作者：
Fersht, AR
影响因子：
14.8
作者：
Strom, Evguenia;Sathe, Swati;Gudkov, Andrei V.
通讯作者：
Gudkov, Andrei V.