Global S&T Development Trend Analysis Platform of Resources and Environment
DOI | 10.1002/fee.1451 |
PTEN counteracts FBXL2 to promote IP3R3-and Ca2+-mediated apoptosis limiting tumour growth | |
Kuchay, Shafi1,2,3; Giorgi, Carlotta1,2,4; Simoneschi, Daniele1,2; Pagan, Julia1,2,3; Missiroli, Sonia4; Saraf, Anita5; Florens, Laurence5; Washburn, Michael P.5,6; Collazo-Lorduy, Ana7,8; Castillo-Martin, Mireia7,9; Cordon-Cardo, Carlos7; Sebti, Said M.10,11; Pinton, Paolo4; Pagano, Michele1,2,3 | |
2017-06-22 | |
发表期刊 | NATURE |
ISSN | 0028-0836 |
EISSN | 1476-4687 |
出版年 | 2017 |
卷号 | 546期号:7659页码:554-+ |
文章类型 | Article |
语种 | 英语 |
国家 | USA; Italy; Spain; Portugal |
英文摘要 | 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(1). However, persistent Ca2+ release results in mitochondrial Ca2+ overload and consequent apoptosis(2). 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(3)) 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(4). 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(5,6). Similarly, disruption of FBXL2 localization with GGTi-2418, a geranylgeranyl transferase inhibitor(7), 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. |
领域 | 地球科学 ; 气候变化 ; 资源环境 |
收录类别 | SCI-E |
WOS记录号 | WOS:000403814100043 |
WOS关键词 | INOSITOL 1,4,5-TRISPHOSPHATE RECEPTORS ; F-MEDIATED DEGRADATION ; LIVER EPITHELIAL-CELLS ; ENDOPLASMIC-RETICULUM ; TRISPHOSPHATE RECEPTORS ; CALCIUM-RELEASE ; DOWN-REGULATION ; CANCER-THERAPY ; CA2+ RELEASE ; ER |
WOS类目 | Multidisciplinary Sciences |
WOS研究方向 | Science & Technology - Other Topics |
引用统计 | |
文献类型 | 期刊论文 |
条目标识符 | http://119.78.100.173/C666/handle/2XK7JSWQ/31683 |
专题 | 资源环境科学 |
作者单位 | 1.NYU, Sch Med, Dept Biochem & Mol Pharmacol, 522 First Ave,SRB 1107, New York, NY 10016 USA; 2.NYU, Sch Med, Perlmutter Canc Ctr, 522 First Ave,SRB 1107, New York, NY 10016 USA; 3.NYU, Sch Med, Howard Hughes Med Inst, 522 First Ave,SRB 1107, New York, NY 10016 USA; 4.Univ Ferrara, Sect Pathol Oncol & Expt Biol, Lab Technol Adv Therapies LTTA, Dept Morphol Surg & Expt Med, Ferrara, Italy; 5.Stowers Inst Med Res, 1000 East 50th St, Kansas City, MO 64110 USA; 6.Univ Kansas, Med Ctr, Dept Pathol & Lab Med, 3901 Rainbow Blvd, Kansas City, KS 66160 USA; 7.Icahn Sch Med Mt Sinai, Dept Pathol, New York, NY 10029 USA; 8.Spanish Soc Med Oncol, Madrid, Spain; 9.Champalimaud Ctr Unknown, Dept Pathol, Lisbon, Portugal; 10.Univ S Florida, Moffitt Canc Ctr, Drug Discovery Dept, Tampa, FL 33612 USA; 11.Univ S Florida, Dept Oncol Sci, Tampa, FL 33612 USA |
推荐引用方式 GB/T 7714 | Kuchay, Shafi,Giorgi, Carlotta,Simoneschi, Daniele,et al. PTEN counteracts FBXL2 to promote IP3R3-and Ca2+-mediated apoptosis limiting tumour growth[J]. NATURE,2017,546(7659):554-+. |
APA | Kuchay, Shafi.,Giorgi, Carlotta.,Simoneschi, Daniele.,Pagan, Julia.,Missiroli, Sonia.,...&Pagano, Michele.(2017).PTEN counteracts FBXL2 to promote IP3R3-and Ca2+-mediated apoptosis limiting tumour growth.NATURE,546(7659),554-+. |
MLA | Kuchay, Shafi,et al."PTEN counteracts FBXL2 to promote IP3R3-and Ca2+-mediated apoptosis limiting tumour growth".NATURE 546.7659(2017):554-+. |
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