title: Simultaneous targeted activation of Notch1 and Vhl-disruption in the kidney proximal epithelial tubular cells in mice.
abstract: Clear cell renal cell carcinoma (ccRCC) is the most common subtype of kidney cancer, representing approximately 75% of all renal neoplasms. ccRCC is known to be strongly associated with silencing of the von Hippel Lindau (VHL) tumor suppressor gene, yet VHL deficiency alone does not seem to be sufficient to drive the oncogenic transformation of normal renal epithelium and induce renal tumorigenesis. We, and others, have previously suggested that constitutive activation of the Notch signaling pathway, alongside with VHL loss, contribute to the oncogenic features of ccRCC. Here we report a prevailing hyperactivation of the Notch1 receptor in human ccRCC relative to the healthy counterpart. To explore the consequences of the elevated Notch1 signaling observed in ccRCC patient material, we made use of a conditional mouse model based on concurrent ectopic expression of constitutively active Notch1 (NICD1) and deletion of the Vhl gene. Histological examination of the kidneys of the conditional mice demonstrate the existence of nests of dysplastic cells with a clear cytoplasm as a consequence of lipid accumulation, thus displaying a one important hallmark of human ccRCC.
authors: Division of Translational Cancer Research, Department of Laboratory Medicine, Medicon Village, Building 404 A3, Scheelevägen 8, 404A3, 223 63 Lund, Sweden.
authors: Elinn
authors: E
authors: Johansson
authors: Division of Translational Cancer Research, Department of Laboratory Medicine, Medicon Village, Building 404 A3, Scheelevägen 8, 404A3, 223 63 Lund, Sweden.
authors: Birgitte
authors: B
authors: Rönö
authors: Center for Molecular Pathology, Department of Translational Medicine, Skåne University Hospital, 205 02 Malmö, Sweden.
authors: Martin
authors: M
authors: Johansson
authors: Division of Translational Cancer Research, Department of Laboratory Medicine, Medicon Village, Building 404 A3, Scheelevägen 8, 404A3, 223 63 Lund, Sweden.
authors: David
authors: D
authors: Lindgren
authors: Division of Translational Cancer Research, Department of Laboratory Medicine, Medicon Village, Building 404 A3, Scheelevägen 8, 404A3, 223 63 Lund, Sweden.
authors: Christina
authors: C
authors: Möller
authors: Division of Translational Cancer Research, Department of Laboratory Medicine, Medicon Village, Building 404 A3, Scheelevägen 8, 404A3, 223 63 Lund, Sweden.
authors: Håkan
authors: H
authors: Axelson
authors: Division of Translational Cancer Research, Department of Laboratory Medicine, Medicon Village, Building 404 A3, Scheelevägen 8, 404A3, 223 63 Lund, Sweden.
authors: Emma M K
authors: EM
authors: Smith
mesh_terms: D000818:Animals; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D055786:Gene Knockout Techniques; D006801:Humans; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism*; D050356:Lipid Metabolism; D051379:Mice; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051881:Receptor, Notch1 / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human