PTEN counteracts FBXL2 to promote IP3R3- and Ca(2+)-mediated apoptosis limiting tumour growth.
PTEN counteracts FBXL2 to promote IP3R3- and Ca(2+)-mediated apoptosis limiting tumour growth.
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DOI：
10.1038/nature22965
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发表时间：
2017-06-22
期刊：
影响因子：
64.8
通讯作者：
Pagano M
中科院分区：
文献类型：
--
作者：
Kuchay S;Giorgi C;Simoneschi D;Pagan J;Missiroli S;Saraf A;Florens L;Washburn MP;Collazo-Lorduy A;Castillo-Martin M;Cordon-Cardo C;Sebti SM;Pinton P;Pagano M
位于内质网的IP3受体(IP3Rs)可以通过准突触的方式将钙输送到线粒体，从而促进氧化磷酸化，从而响应环境信号促进IP3(1，4，5-三磷酸)的产生。然而，持续的Ca~(2+)释放会导致线粒体Ca~(2+)超载而导致细胞凋亡。在三种哺乳动物的IP3R中，IP3R3似乎是钙依赖性细胞凋亡的主要参与者。在这里，我们发现F-box蛋白Fbxl2(69个人类SCF(Skp1，CUL1，F-box蛋白)泛素连接酶复合体之一的受体亚单位)与IP3R3结合，并以泛素、p97和蛋白酶体介导的降解为靶点，以限制钙离子进入线粒体。Fbxl2-基因敲除细胞和Fbxl2-不敏感的IP3R3基因敲入突变克隆表现出胞浆内钙离子从内质网释放增加，并对钙依赖的凋亡刺激敏感。磷酸酶和紧张素同源基因(PTEN)在人类易患癌症的肿瘤和综合征中经常发生突变或丢失。我们发现PTEN与Fbxl2竞争IP3R3结合，在Pten−/−小鼠胚胎成纤维细胞和PTEN缺失的癌细胞中，依赖Fbxl2的IP3R3的降解被加速。用野生型PTEN或催化死亡突变体重组PTEN缺失细胞可以稳定IP3R3，并诱导持久的钙动员和细胞凋亡。在人类前列腺癌中，IP3R3和PTEN蛋白水平直接相关。在细胞培养和异种移植模型中，不可降解的IP3R3突变体使低表达或不表达PTEN的肿瘤细胞对光动力疗法敏感，这是基于光敏剂药物在可见光照射后引起钙依赖的细胞毒性的能力。同样，香叶基香叶基转移酶抑制剂GGTI-2418阻断Fbxl2的定位，会使异种移植瘤对光动力疗法敏感。综上所述，我们确定了一个新的分子机制，限制线粒体钙超载，以防止细胞死亡。值得注意的是，我们提供了抑制PTEN基因缺失的癌症中IP3R3降解的原则证据，这是一种有效的治疗策略。
In response to environmental cues that promote IP3 (inositol 1,4,5-trisphosphate) generation, IP3 receptors (IP3Rs) located on the endoplasmic reticulum allow the ‘quasisynaptical’ feeding of calcium to the mitochondria to promote oxidative phosphorylation. However, persistent Ca2+ release results in mitochondrial Ca2+ overload and consequent apoptosis. Among the three mammalian IP3Rs, IP3R3 appears to be the major player in Ca2+-dependent apoptosis. Here we show that the F-box protein FBXL2 (the receptor subunit of one of 69 human SCF (SKP1, CUL1, F-box protein) ubiquitin ligase complexes) binds IP3R3 and targets it for ubiquitin-, p97- and proteasome-mediated degradation to limit Ca2+ influx into mitochondria. FBXL2-knockdown cells and FBXL2-insensitive IP3R3 mutant knock-in clones display increased cytosolic Ca2+ release from the endoplasmic reticulum and sensitization to Ca2+-dependent apoptotic stimuli. The phosphatase and tensin homologue (PTEN) gene is frequently mutated or lost in human tumours and syndromes that predispose individuals to cancer. We found that PTEN competes with FBXL2 for IP3R3 binding, and the FBXL2-dependent degradation of IP3R3 is accelerated in Pten−/− mouse embryonic fibroblasts and PTEN-null cancer cells. Reconstitution of PTEN-null cells with either wild-type PTEN or a catalytically dead mutant stabilizes IP3R3 and induces persistent Ca2+ mobilization and apoptosis. IP3R3 and PTEN protein levels directly correlate in human prostate cancer. Both in cell culture and xenograft models, a non-degradable IP3R3 mutant sensitizes tumour cells with low or no PTEN expression to photodynamic therapy, which is based on the ability of photosensitizer drugs to cause Ca2+-dependent cytotoxicity after irradiation with visible light. Similarly, disruption of FBXL2 localization with GGTi-2418, a geranylgeranyl transferase inhibitor, sensitizes xenotransplanted tumours to photodynamic therapy. In summary, we identify a novel molecular mechanism that limits mitochondrial Ca2+ overload to prevent cell death. Notably, we provide proof-of-principle that inhibiting IP3R3 degradation in PTEN-deregulated cancers represents a valid therapeutic strategy.
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影响因子：
64.8
作者：
Fan G;Baker ML;Wang Z;Baker MR;Sinyagovskiy PA;Chiu W;Ludtke SJ;Serysheva II
通讯作者：
Serysheva II
DOI：
10.1126/science.1189157
发表时间：
2010-11-26
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Giorgi C;Ito K;Lin HK;Santangelo C;Wieckowski MR;Lebiedzinska M;Bononi A;Bonora M;Duszynski J;Bernardi R;Rizzuto R;Tacchetti C;Pinton P;Pandolfi PP
通讯作者：
Pandolfi PP
影响因子：
16
作者：
Dankert, John F.;Rona, Gergely;Clijsters, Linda;Geter, Phillip;Skaar, Jeffrey R.;Bermudez-Hernandez, Keria;Sassani, Elizabeth;Fenyo, David;Ueberheide, Beatrix;Schneider, Robert;Pagano, Michele
通讯作者：
Pagano, Michele
影响因子：
16.8
作者：
通讯作者：
--
影响因子：
4.8
作者：
Bokkala, S;Joseph, SK
通讯作者：
Joseph, SK