UV irradiation resistance-associated gene suppresses apoptosis by interfering with BAX activation

• Published in: EMBO reports 2011-07, Vol.12 (7), p.727-734
• Main Authors: Yin, Xiaocheng, Cao, Lizhi, Kang, Rui, Yang, Minghua, Wang, Zhuo, Peng, Yanhui, Tan, Yanfang, Liu, Liying, Xie, Min, Zhao, Yiming, Livesey, Kristen M, Tang, Daolin
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Apoptosis - genetics; autophagy; BAX; bcl-2-Associated X Protein - genetics; bcl-2-Associated X Protein - metabolism; Cell Line, Tumor; Chemotherapy; Cytochrome; Drug Resistance, Neoplasm - genetics; EMBO07; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Gene Expression Regulation, Neoplastic - radiation effects; HCT116 Cells; HeLa Cells; HL-60 Cells; Humans; Irradiation; Mice; Mice, Nude; Mitochondria; Mitochondria - metabolism; Molecular biology; Mutagens - pharmacology; Protein Binding - physiology; Protein Transport - genetics; Proteins; Radiation Tolerance - genetics; Scientific Report; Scientific Reports; Translocation; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Tumors; Ultraviolet radiation; Ultraviolet Rays
• ISSN: 1469-221X; 1469-3178
• DOI: 10.1038/embor.2011.79

Ultraviolet irradiation resistance‐associated gene ( UVRAG ) is a well‐known regulator of autophagy by promoting autophagosome formation and maturation. However, little is known about the non‐autophagic functions of UVRAG. Here, we present evidence that UVRAG functions as an unusual BCL2‐associated X protein (Bax) suppressor to regulate apoptosis. Chemotherapy and radiation induces UVRAG expression and subsequently upregulates autophagy and apoptosis in tumour cells. Depletion of UVRAG expression by RNA interference renders tumour cells more sensitive to chemotherapy‐ and radiation‐induced apoptosis in vitro and in vivo . Moreover, UVRAG interacts with Bax, which inhibits apoptotic stimuli‐induced mitochondrial translocation of Bax, reduction of mitochondrial membrane potential, cytochrome c release and activation of caspase‐9 and ‐3. Our findings show that UVRAG has an essential role in the intrinsic mitochondrial pathway of apoptosis by regulating the localization of Bax. This pathway represents a target for clinical intervention against tumours. In addition to its role in autophagy, this report shows that UVRAG has a cytoprotective function in the cytosol by preventing mitochondrial translocation of BAX and subsequent activation of cell death when tumour cells are subjected to apoptotic stimuli.