SPOP promotes ATF2 ubiquitination and degradation to suppress prostate cancer progression.
SPOP promotes ATF2 ubiquitination and degradation to suppress prostate cancer progression.
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SPOP 促进 ATF2 泛素化和降解以抑制前列腺癌进展
DOI：
10.1186/s13046-018-0809-0
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发表时间：
2018-07-11
期刊：
影响因子：
--
通讯作者：
Wang C
中科院分区：
文献类型：
--
作者：
Ma J;Chang K;Peng J;Shi Q;Gan H;Gao K;Feng K;Xu F;Zhang H;Dai B;Zhu Y;Shi G;Shen Y;Zhu Y;Qin X;Li Y;Zhang P;Ye D;Wang C
研究背景新一代前列腺癌外显子组和基因组测序发现了大量的基因突变，SPOP（Speckle-type POZ Protein）是原发性前列腺癌中最常见的突变基因之一，提示SPOP可能是前列腺癌的潜在驱动因子.这项工作的目的是调查如何SPOP突变有助于前列腺癌的发展和progress.MethodsTo确定肿瘤抑制功能的SPOP的分子介质，我们进行了酵母双杂交筛选HeLa cDNA文库中使用全长SPOP作为诱饵。采用免疫沉淀法和Western Blotting法分析SPOP与ATF 2的相互作用。细胞迁移和侵袭通过Transwell测定。免疫组化被用来分析患者的肿瘤samples.ResultsHere蛋白水平，我们确定了ATF 2作为一个真正的底物的SPOP-CUL 3-RBX 1 E3泛素连接酶复合物。SPOP识别ATF 2中多个富含Ser/Thr（S/T）的降解决定子，并通过泛素-蛋白酶体途径触发ATF 2降解。引人注目的是，前列腺癌相关突变体的SPOP是缺陷的，在促进ATF 2降解前列腺癌细胞，并有助于促进前列腺癌细胞的增殖，迁移和invasion.ConclusionSPOP促进ATF 2泛素化和降解，和ATF 2是一个重要的介质SPOP失活诱导细胞增殖，迁移和侵袭。
BackgroundNext-generation sequencing of the exome and genome of prostate cancers has identified numerous genetic alterations.SPOP(Speckle-type POZ Protein) is one of the most frequently mutated genes in primary prostate cancer, suggesting thatSPOPmay be a potential driver of prostate cancer. The aim of this work was to investigate how SPOP mutations contribute to prostate cancer development and progression.MethodsTo identify molecular mediators of the tumor suppressive function of SPOP, we performed a yeast two-hybrid screen in a HeLa cDNA library using the full-length SPOP as bait. Immunoprecipitation and Western Blotting were used to analyze the interaction between SPOP and ATF2. Cell migration and invasion were determined by Transwell assays. Immunohistochemistry were used to analyze protein levels in patients’ tumor samples.ResultsHere we identified ATF2 as a bona fide substrate of the SPOP-CUL3-RBX1 E3 ubiquitin ligase complex. SPOP recognizes multiple Ser/Thr (S/T)-rich degrons in ATF2 and triggers ATF2 degradation via the ubiquitin-proteasome pathway. Strikingly, prostate cancer-associated mutants of SPOP are defective in promoting ATF2 degradation in prostate cancer cells and contribute to facilitating prostate cancer cell proliferation, migration and invasion.ConclusionSPOP promotes ATF2 ubiquitination and degradation, and ATF2 is an important mediator of SPOP inactivation-induced cell proliferation, migration and invasion.
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影响因子：
64.5
作者：
Cancer Genome Atlas Research Network
通讯作者：
Cancer Genome Atlas Research Network
影响因子：
82.9
作者：
Dai X;Gan W;Li X;Wang S;Zhang W;Huang L;Liu S;Zhong Q;Guo J;Zhang J;Chen T;Shimizu K;Beca F;Blattner M;Vasudevan D;Buckley DL;Qi J;Buser L;Liu P;Inuzuka H;Beck AH;Wang L;Wild PJ;Garraway LA;Rubin MA;Barbieri CE;Wong KK;Muthuswamy SK;Huang J;Chen Y;Bradner JE;Wei W
通讯作者：
Wei W
影响因子：
16
作者：
Gan W;Dai X;Lunardi A;Li Z;Inuzuka H;Liu P;Varmeh S;Zhang J;Cheng L;Sun Y;Asara JM;Beck AH;Huang J;Pandolfi PP;Wei W
通讯作者：
Wei W
影响因子：
4.8
作者：
Blattner, Mirjam;Lee, Daniel J.;Rubin, Mark A.
通讯作者：
Rubin, Mark A.
影响因子：
82.9
作者：
Janouskova H;El Tekle G;Bellini E;Udeshi ND;Rinaldi A;Ulbricht A;Bernasocchi T;Civenni G;Losa M;Svinkina T;Bielski CM;Kryukov GV;Cascione L;Napoli S;Enchev RI;Mutch DG;Carney ME;Berchuck A;Winterhoff BJN;Broaddus RR;Schraml P;Moch H;Bertoni F;Catapano CV;Peter M;Carr SA;Garraway LA;Wild PJ;Theurillat JP
通讯作者：
Theurillat JP