title: Stem-cell-specific endocytic degradation defects lead to intestinal dysplasia in Drosophila.
abstract: UV 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.
authors.affiliation: Department of Anatomy, Cell and Developmental Biology, Eötvös Loránd University, Pázmány s. 1/C, Budapest H-1117, Hungary.
authors.forename: Péter
authors.initials: P
authors.lastname: Nagy
authors.affiliation: Department of Anatomy, Cell and Developmental Biology, Eötvös Loránd University, Pázmány s. 1/C, Budapest H-1117, Hungary.
authors.forename: Laura
authors.initials: L
authors.lastname: Kovács
authors.affiliation: Department of Anatomy, Cell and Developmental Biology, Eötvös Loránd University, Pázmány s. 1/C, Budapest H-1117, Hungary.
authors.forename: Gyöngyvér O
authors.initials: GO
authors.lastname: Sándor
authors.affiliation: Department of Anatomy, Cell and Developmental Biology, Eötvös Loránd University, Pázmány s. 1/C, Budapest H-1117, Hungary Institute of Genetics, Biological Research Centre of the Hungarian Academy of Sciences, Temesvári krt. 62, Szeged H-6726, Hungary szmrt@elte.hu.
authors.forename: Gábor
authors.identifier: 0000-0001-8548-8874
authors.initials: G
authors.lastname: Juhász
mesh_terms: D000818:Animals; D001343:Autophagy; D002454:Cell Differentiation; D049109:Cell Proliferation; D048430:Cell Shape; D029721:Drosophila Proteins / Q000378:metabolism; D004331:Drosophila melanogaster / Q000166:cytology* / Q000378:metabolism*; D004705:Endocytosis; D011992:Endosomes / Q000378:metabolism*; D006801:Humans; D007422:Intestines / Q000473:pathology*; D008954:Models, Biological; D059748:Proteolysis; D051880:Receptors, Notch / Q000378:metabolism; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*; D013312:Stress, Physiological; D016019:Survival Analysis; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D029721:Drosophila Proteins; D051880:Receptors, Notch; D050791:STAT Transcription Factors; D025521:Tumor Suppressor Proteins; C561319:UVRAG protein, Drosophila
keywords: Autophagy; Drosophila; Endocytosis; UVRAG