title: Brain-expressed X-linked 2 Is Pivotal for Hyperactive Mechanistic Target of Rapamycin (mTOR)-mediated Tumorigenesis.
abstract: Frequent alteration of upstream proto-oncogenes and tumor suppressor genes activates mechanistic target of rapamycin (mTOR) and causes cancer. However, the downstream effectors of mTOR remain largely elusive. Here we report that brain-expressed X-linked 2 (BEX2) is a novel downstream effector of mTOR. Elevated BEX2 in Tsc2(-/-) mouse embryonic fibroblasts, Pten(-/-) mouse embryonic fibroblasts, Tsc2-deficient rat uterine leiomyoma cells, and brains of neuronal specific Tsc1 knock-out mice were abolished by mTOR inhibitor rapamycin. Furthermore, BEX2 was also increased in the liver of a hepatic specific Pten knock-out mouse and the kidneys of Tsc2 heterozygous deletion mice, and a patient with tuberous sclerosis complex (TSC). mTOR up-regulation of BEX2 was mediated in parallel by both STAT3 and NF-κB. BEX2 was involved in mTOR up-regulation of VEGF production and angiogenesis. Depletion of BEX2 blunted the tumorigenesis of cells with activated mTOR. Therefore, enhanced STAT3/NF-κB-BEX2-VEGF signaling pathway contributes to hyperactive mTOR-induced tumorigenesis. BEX2 may be targeted for the treatment of the cancers with aberrantly activated mTOR signaling pathway.
authors: From the State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China, the Modern Research Center for Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China.
authors: Zhongdong
authors: Z
authors: Hu
authors: the Department of Molecular Orthopaedics, Beijing Institute of Traumatology and Orthopaedics, Beijing Jishuitan Hospital, Beijing 100035, China.
authors: Ying
authors: Y
authors: Wang
authors: From the State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China.
authors: Fuqiang
authors: F
authors: Huang
authors: From the State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China.
authors: Rongrong
authors: R
authors: Chen
authors: From the State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China.
authors: Chunjia
authors: C
authors: Li
authors: From the State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China.
authors: Fang
authors: F
authors: Wang
authors: the Division of Pediatric Neurosurgery, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229.
authors: June
authors: J
authors: Goto
authors: the Division of Translational Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115.
authors: David J
authors: DJ
authors: Kwiatkowski
authors: the Institut de Chimie des Substances Naturelles, CNRS UPR2301, 91198 Gif sur Yvette, France.
authors: Joanna
authors: J
authors: Wdzieczak-Bakala
authors: the Modern Research Center for Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China.
authors: Pengfei
authors: P
authors: Tu
authors: the Sino-France Laboratory for Drug Screening, Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China.
authors: Jianmiao
authors: J
authors: Liu
authors: the Department of Biochemistry and Molecular Biology, School of Basic Medicine, Anhui Medical University, Hefei 230032, China, and the State Key Laboratory Incubation Base of Dermatology, Ministry of National Science and Technology, Hefei 230032, China zhaxiaojunpumc@gmail.com.
authors: Xiaojun
authors: X
authors: Zha
authors: From the State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China, hbzhang@ibms.pumc.edu.cn hbzhang2006@gmail.com.
authors: Hongbing
authors: H
authors: Zhang
mesh_terms: D000818:Animals; D063646:Carcinogenesis; D002478:Cells, Cultured; D006801:Humans; D007680:Kidney Neoplasms / Q000209:etiology / Q000473:pathology; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D034741:RNA, Small Interfering / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism / Q000502:physiology*; D015854:Up-Regulation
chemical_list: C502261:Bex2 protein, mouse; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases
keywords: BEX2; NF-kappa B (NF-KB); STAT3; mammalian target of rapamycin (mTOR); signal transduction; tuberous sclerosis complex (TSC); tumorigenesis; vascular endothelial growth factor (VEGF)