Pivotal role of augmented αB-crystallin in tumor development induced by deficient TSC1/2 complex.
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.
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.
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Wang
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.
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Chen
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.
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Li
Department of Immunology, Tianjin Cancer Institute and Hospital, Tianjin Medical University, Tianjin, China.
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Sun
Center for Coronary Heart Disease, Cardiovascular Institute and Fu Wai Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
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Chen
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.
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Wang
Department of Cancer Biology, The Scripps Research Institute, Jupiter, FL, USA.
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Peng
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.
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Liu
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.
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Chen
Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China.
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Liu
Center for Coronary Heart Disease, Cardiovascular Institute and Fu Wai Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
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Yan
Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY, USA.
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Ye
Division of Translational Medicine, Brigham and Women's Hospital and Dana-Faber Cancer Institute, Harvard Medical School, Boston, MA, USA.
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Kwiatkowski
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.
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Zhang
D000818:Animals; D017209:Apoptosis; D063646:Carcinogenesis / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms / Q000378:metabolism; D007889:Leiomyoma / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism; D018192:Lymphangioleiomyomatosis / Q000378:metabolism; D008297:Male; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009368:Neoplasm Transplantation; D051381:Rats; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014402:Tuberous Sclerosis / Q000378:metabolism; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000172:deficiency*; D014594:Uterine Neoplasms / Q000378:metabolism; D038203:alpha-Crystallin B Chain / Q000502:physiology*
D046912:Multiprotein Complexes; D016328:NF-kappa B; C000624650:TSC1 protein, human; C000624653:TSC2 protein, human; C000624651:Tsc1 protein, mouse; C000624652:Tsc1 protein, rat; C000624654:Tsc2 protein, mouse; C000624655:Tsc2 protein, rat; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D038203:alpha-Crystallin B Chain; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases