State Key Laboratory of Medical Molecular Biology, Department of Physiology and Pathophysiology, Institute of Basic Medical Sciences and School of Basic Medicine, Graduate School of Peking Union Medical College, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
Department of Immunology, Tianjin Cancer Institute and Hospital, Tianjin Medical University, Tianjin, China.
Oncogene. 2014 Aug 21;33(34):4352-8. doi: 10.1038/onc.2013.401. Epub 2013 Sep 30.
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.
结节性硬化症复合物 1（TSC1）和 TSC2 是雷帕霉素靶蛋白（mTOR）的机械靶点抑制剂。mTOR 是两种蛋白复合物的主要组成部分：mTOR 复合物 1（mTORC1）和 mTORC2。TSC1 或 TSC2 的无活性突变会释放 mTOR 信号，从而导致 TSC，这是一种影响多个器官的良性肿瘤综合征。我们在这里报告，αB-晶状体蛋白在 Tsc1-/-或 Tsc2-/-小鼠胚胎成纤维细胞、Eker 大鼠子宫平滑肌瘤衍生的 Tsc2 缺陷型 ELT3 细胞、突变 Tsc2 相关的小鼠肾肿瘤和人类肺淋巴管平滑肌瘤病结节中上调表达。αB-晶状体蛋白被 mTOR 复合物 2（mTORC2）：核因子-kappa B（NFκB）信号级联转录激活。增强的 αB-晶状体蛋白对于 Tsc2 缺陷细胞的迁移、侵袭和抗凋亡至关重要。αB-晶状体蛋白的破坏抑制了 Tsc2 缺失细胞的增殖和肿瘤发生。因此，增强的 αB-晶状体蛋白在 TSC1/2 复合物缺陷介导的肿瘤发生中具有重要作用，抑制 αB-晶状体蛋白可能补充 TSC 的当前治疗方法。
