Stem-cell-specific endocytic degradation defects lead to intestinal dysplasia in Drosophila
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 prolif...
| الحاوية / القاعدة: | Disease Models & Mechanisms |
|---|---|
| المؤلفون الرئيسيون: | , , , |
| التنسيق: | مقال |
| اللغة: | الإنجليزية |
| منشور في: |
The Company of Biologists
2016-05-01
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| الموضوعات: | |
| الوصول للمادة أونلاين: | http://dmm.biologists.org/content/9/5/501 |
| _version_ | 1852798454370140160 |
|---|---|
| author | Péter Nagy Laura Kovács Gyöngyvér O. Sándor Gábor Juhász |
| author_facet | Péter Nagy Laura Kovács Gyöngyvér O. Sándor Gábor Juhász |
| author_sort | Péter Nagy |
| collection | DOAJ |
| container_title | Disease Models & Mechanisms |
| description | 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. |
| format | Article |
| id | doaj-art-074f13e69e4c491caa4a3e2144bd8f8d |
| institution | Directory of Open Access Journals |
| issn | 1754-8403 1754-8411 |
| language | English |
| publishDate | 2016-05-01 |
| publisher | The Company of Biologists |
| record_format | Article |
| spelling | doaj-art-074f13e69e4c491caa4a3e2144bd8f8d2025-08-19T20:41:02ZengThe Company of BiologistsDisease Models & Mechanisms1754-84031754-84112016-05-019550151210.1242/dmm.023416023416Stem-cell-specific endocytic degradation defects lead to intestinal dysplasia in DrosophilaPéter Nagy0Laura Kovács1Gyöngyvér O. Sándor2Gábor Juhász3 Department of Anatomy, Cell and Developmental Biology, Eötvös Loránd University, Pázmány s. 1/C, Budapest H-1117, Hungary Department of Anatomy, Cell and Developmental Biology, Eötvös Loránd University, Pázmány s. 1/C, Budapest H-1117, Hungary Department of Anatomy, Cell and Developmental Biology, Eötvös Loránd University, Pázmány s. 1/C, Budapest H-1117, Hungary Department of Anatomy, Cell and Developmental Biology, Eötvös Loránd University, Pázmány s. 1/C, Budapest H-1117, Hungary 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.http://dmm.biologists.org/content/9/5/501AutophagyDrosophilaEndocytosisUVRAG |
| spellingShingle | Péter Nagy Laura Kovács Gyöngyvér O. Sándor Gábor Juhász Stem-cell-specific endocytic degradation defects lead to intestinal dysplasia in Drosophila Autophagy Drosophila Endocytosis UVRAG |
| title | Stem-cell-specific endocytic degradation defects lead to intestinal dysplasia in Drosophila |
| title_full | Stem-cell-specific endocytic degradation defects lead to intestinal dysplasia in Drosophila |
| title_fullStr | Stem-cell-specific endocytic degradation defects lead to intestinal dysplasia in Drosophila |
| title_full_unstemmed | Stem-cell-specific endocytic degradation defects lead to intestinal dysplasia in Drosophila |
| title_short | Stem-cell-specific endocytic degradation defects lead to intestinal dysplasia in Drosophila |
| title_sort | stem cell specific endocytic degradation defects lead to intestinal dysplasia in drosophila |
| topic | Autophagy Drosophila Endocytosis UVRAG |
| url | http://dmm.biologists.org/content/9/5/501 |
| work_keys_str_mv | AT peternagy stemcellspecificendocyticdegradationdefectsleadtointestinaldysplasiaindrosophila AT laurakovacs stemcellspecificendocyticdegradationdefectsleadtointestinaldysplasiaindrosophila AT gyongyverosandor stemcellspecificendocyticdegradationdefectsleadtointestinaldysplasiaindrosophila AT gaborjuhasz stemcellspecificendocyticdegradationdefectsleadtointestinaldysplasiaindrosophila |