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: Zhongdong Hu, Ying Wang, Fuqiang Huang, Rongrong Chen, Chunjia Li, Fang Wang, June Goto, David J Kwiatkowski, Joanna Wdzieczak-Bakala, Pengfei Tu, Jianmiao Liu, Xiaojun Zha, Hongbing Zhang
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 290 Issue 42 Pg. 25756-65 (Oct 16 2015) ISSN: 1083-351X [Electronic] United States
• PMID: 26296882 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• Bex2 protein, mouse
• NF-kappa B
• Nerve Tissue Proteins
• RNA, Small Interfering
• STAT3 Transcription Factor
• Stat3 protein, mouse
• mTOR protein, mouse
• TOR Serine-Threonine Kinases

Topics

• Animals
• Carcinogenesis
• Cells, Cultured
• Humans
• Kidney Neoplasms (etiology, pathology)
• Mice
• NF-kappa B (metabolism)
• Nerve Tissue Proteins (genetics, metabolism, physiology)
• RNA, Small Interfering (genetics)
• STAT3 Transcription Factor (metabolism)
• TOR Serine-Threonine Kinases (metabolism, physiology)
• Up-Regulation