Abstract
ABSTRACTUV radiation resistance-associated gene (UVRAG) is a tumor suppressor involved in autophagy, endocytosis and DNA damage repair, but how its loss contributes to colorectal cancer is poorly understood. Here, we show that UVRAG deficiency in Drosophila intestinal stem cells leads to uncontrolled proliferation and impaired differentiation without preventing autophagy. As a result, affected animals suffer from gut dysfunction and short lifespan. Dysplasia upon loss of UVRAG is characterized by the accumulation of endocytosed ligands and sustained activation of STAT and JNK signaling, and attenuation of these pathways suppresses stem cell hyperproliferation. Importantly, the inhibition of early (dynamin-dependent) or late (Rab7-dependent) steps of endocytosis in intestinal stem cells also induces hyperproliferation and dysplasia. Our data raise the possibility that endocytic, but not autophagic, defects contribute to UVRAG-deficient colorectal cancer development in humans.
Highlights
UV radiation resistance-associated gene (UVRAG) encodes a subunit of the Vps34 kinase complex, which is important for the generation of phosphatidylinositol 3-phosphate (PI3P)
UVRAG was originally found to have dual roles in autophagy through promotion of autophagosome formation and fusion with lysosomes in various cultured cell lines based on, predominantly, overexpression experiments (Liang et al, 2006, 2008), recent reports have described that autophagosomes are normally generated and fused with lysosomes in the absence of UVRAG in cultured mammalian (HeLa) cells and in the Drosophila fat body (Jiang et al, 2014; Takáts et al, 2014)
The discoveries of UVRAG mutations in colorectal cancer cells, and that its overexpression increases autophagy and suppresses the proliferation of certain cancer cell lines, altogether suggest that this gene functions as an autophagic tumor suppressor (Ionov et al, 2004; Liang et al, 2006). Such a role for UVRAG is thought to be related to its binding to Beclin 1, a haploinsufficient tumor suppressor gene required for autophagy (Qu et al, 2003; Yue et al, 2003)
Summary
UV radiation resistance-associated gene (UVRAG) encodes a subunit of the Vps kinase complex, which is important for the generation of phosphatidylinositol 3-phosphate (PI3P). UVRAG promotes the biogenesis of this phospholipid by binding to the autophagic tumor suppressor Beclin-1 within this complex (Itakura et al, 2008; Liang et al, 2006). UVRAG is reported to bind to HOPS (Liang et al, 2008), a tethering complex that promotes multiple trafficking routes to lysosomes, including autophagy, endocytosis, and the biosynthetic transport of hydrolytic enzymes and membrane proteins. Overexpression of UVRAG is found to promote autophagy and reduce cell proliferation, raising the possibility that its tumor suppressor function involves the regulation of autophagy (Liang et al, 2006). In line with that possibility, transposon-induced Uvrag-mutant mice display impaired autophagic degradation in cardiomyocytes and fibroblasts
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