Department of Pediatrics, The First Affiliated Hospital of Nanhua University, Hengyang, Hunan 421001, People's Republic of China.
EMBO Rep. 2011 Jul 1;12(7):727-34. 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.
紫外线照射抵抗相关基因（UVRAG）是一种通过促进自噬体形成和成熟来调节自噬的著名调控因子。然而，人们对 UVRAG 的非自噬功能知之甚少。在这里，我们提供的证据表明，UVRAG 作为一种不寻常的 BCL2 相关 X 蛋白（Bax）抑制因子发挥作用，以调节细胞凋亡。化疗和放疗诱导 UVRAG 表达，随后上调肿瘤细胞中的自噬和细胞凋亡。通过 RNA 干扰耗尽 UVRAG 表达可使肿瘤细胞在体外和体内对化疗和放疗诱导的细胞凋亡更加敏感。此外，UVRAG 与 Bax 相互作用，抑制凋亡刺激诱导的 Bax 在线粒体中的易位、线粒体膜电位的降低、细胞色素 c 的释放以及 caspase-9 和 caspase-3 的激活。我们的研究结果表明，UVRAG 通过调节 Bax 的定位在细胞凋亡的固有线粒体途径中发挥重要作用。该途径代表了针对肿瘤的临床干预的靶点。
