TSGΔ154-1054 splice variant increases TSG101 oncogenicity by inhibiting its E3-ligase-mediated proteasomal degradation.
TSGΔ154-1054 splice variant increases TSG101 oncogenicity by inhibiting its E3-ligase-mediated proteasomal degradation.
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DOI：
10.18632/oncotarget.6973
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发表时间：
2016-02-16
期刊：
影响因子：
--
通讯作者：
Yeh TH
中科院分区：
文献类型：
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作者：
Chua HH;Huang CS;Weng PL;Yeh TH
肿瘤易感基因 101 (TSG101) 引发一系列细胞功能，包括促进胞质分裂、细胞周期进程和增殖，以及促进内体运输和病毒出芽。 TSG101 蛋白在多种人类癌症中高度异常表达。具体而言，TSG101 剪接变异体缺失了 154 至 1054 个核苷酸（TSGΔ154-1054），它与进展性肿瘤分期和转移有关，十多年来一直困扰着研究人员。 TSG101 相关的 E3 连接酶 (Tal) 和 MDM2 介导的蛋白酶体降解是 TSG101 总量翻译后调节的两条主要途径。我们发现，TSG101 过量是由于 TSGΔ154-1054 通过竞争性结合 Tal 而不是 MDM2 来稳定 TSG101 蛋白，从而扰乱 Tal 与 TSG101 的相互作用，并阻碍随后的 TSG101 多泛素化和蛋白酶体降解。因此，TSGΔ154-1054 特异性增强裸鼠中 TSG101 刺激的细胞增殖、克隆形成和肿瘤生长。这一发现显示了 TSGΔ154-1054 在阻止 TSG101 泛素蛋白酶体蛋白水解方面的功能意义，TSG101 会增加肿瘤的恶性程度，并暗示其作为癌症治疗靶点的潜力。
Tumor susceptibility gene 101 (TSG101) elicits an array of cellular functions, including promoting cytokinesis, cell cycle progression and proliferation, as well as facilitating endosomal trafficking and viral budding. TSG101 protein is highly and aberrantly expressed in various human cancers. Specifically, a TSG101 splicing variant missing nucleotides 154 to 1054 (TSGΔ154-1054), which is linked to progressive tumor-stage and metastasis, has puzzled investigators for more than a decade. TSG101-associated E3 ligase (Tal)- and MDM2-mediated proteasomal degradation are the two major routes for posttranslational regulation of the total amount of TSG101. We reveal that overabundance of TSG101 results from TSGΔ154-1054 stabilizing the TSG101 protein by competitively binding to Tal, but not MDM2, thereby perturbing the Tal interaction with TSG101 and impeding subsequent polyubiquitination and proteasomal degradation of TSG101. TSGΔ154-1054 therefore specifically enhances TSG101-stimulated cell proliferation, clonogenicity, and tumor growth in nude mice. This finding shows the functional significance of TSGΔ154-1054 in preventing the ubiquitin-proteasome proteolysis of TSG101, which increases tumor malignancy and hints at its potential as a therapeutic target in cancer treatment.