Pivotal role of augmented αB-crystallin in tumor development induced by deficient TSC1/2 complex
Pivotal role of augmented αB-crystallin in tumor development induced by deficient TSC1/2 complex
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DOI：
10.1038/onc.2013.401
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发表时间：
2014-08
期刊：
影响因子：
8
通讯作者：
Feng Wang;X. Chen;Chunxiao Li;Q. Sun;Yangpeng Chen;Yan Wang;Haiyong Peng;Zhihua Liu;Runsheng Chen;Kangdong Liu;H. Yan;B. Ye;David J. Kwiatkowski;Hongbin Zhang
中科院分区：
文献类型：
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作者：
Feng Wang;X. Chen;Chunxiao Li;Q. Sun;Yangpeng Chen;Yan Wang;Haiyong Peng;Zhihua Liu;Runsheng Chen;Kangdong Liu;H. Yan;B. Ye;David J. Kwiatkowski;Hongbin Zhang
结节性硬化症复合体1(TSC1)和TSC2是雷帕霉素机制靶点(MTOR)的抑制因子。MTOR是两种蛋白质复合体的主要成分：mTOR复合体1(MTORC1)和mTORC2。TSC1或TSC2的非活性突变会释放mTOR信号，从而导致TSC，一种影响多个器官的良性肿瘤综合征。我们在此报道了αB-晶体蛋白在小鼠胚胎成纤维细胞、Eker大鼠子宫肌瘤来源的−/−缺陷细胞、突变的Tsc2相关小鼠肾肿瘤和人肺淋巴管肌瘤病结节中的表达上调。αB-晶状体蛋白被mTORC2：核因子-kappaB(NF-κB)信号转导通路激活。增强的αB-晶状体蛋白对TSC2缺陷细胞的迁移、侵袭和抗凋亡起关键作用。αB-晶体蛋白的破坏抑制了TSC2零细胞的增殖和肿瘤的发生。因此，增强的αB-晶体蛋白在α1/2复合体缺陷介导的肿瘤发生中具有重要作用，抑制TSCB-晶体蛋白可能是对目前治疗的补充。
Tuberous sclerosis complex 1 (TSC1) and TSC2 are suppressors of mechanistic target of rapamycin (mTOR). mTOR is the major component of two protein complexes: mTOR complex 1 (mTORC1) and mTORC2. Inactive mutation of either TSC1 or TSC2 unleashes mTOR signaling and consequently causes TSC, a benign tumor syndrome affecting multiple organs. We report here that expression of αB-crystallin was upregulated in Tsc1−/− or Tsc2−/− mouse embryonic fibroblasts, Eker rat uterine leiomyoma-derived Tsc2-deficient ELT3 cells, mutant Tsc2-associated mouse kidney tumors, and human lung lymphangioleiomyomatosis nodules. αB-crystallin was transcriptionally activated by mTOR complex 2 (mTORC2): nuclear factor-kappa B (NFκB) signaling cascade. The augmented αB-crystallin was critical for the migration, invasion and apoptotic resistance of Tsc2-defective cells. Disruption of αB-crystallin suppressed Tsc2-null cell proliferation and tumorigenesis. Therefore, enhanced αB-crystallin has an essential role in TSC1/2 complex deficiency-mediated tumorigenesis, and inhibition of αB-crystallin may complement the current therapy for TSC.