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Combined mutation of Vhl and Trp53 causes renal cysts and tumours in mice

The combinations of genetic alterations that cooperate with von Hippel–Lindau (VHL) mutation to cause clear cell renal cell carcinoma (ccRCC) remain poorly understood. We show that the TP53 tumour suppressor gene is mutated in approximately 9% of human ccRCCs. Combined deletion of Vhl and Trp53 in p...

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Autores principales: Albers, Joachim, Rajski, Michal, Schönenberger, Désirée, Harlander, Sabine, Schraml, Peter, von Teichman, Adriana, Georgiev, Strahil, Wild, Peter J, Moch, Holger, Krek, Wilhelm, Frew, Ian J
Formato: Online Artículo Texto
Lenguaje:English
Publicado: WILEY-VCH Verlag 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3779454/
https://www.ncbi.nlm.nih.gov/pubmed/23606570
http://dx.doi.org/10.1002/emmm.201202231
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author Albers, Joachim
Rajski, Michal
Schönenberger, Désirée
Harlander, Sabine
Schraml, Peter
von Teichman, Adriana
Georgiev, Strahil
Wild, Peter J
Moch, Holger
Krek, Wilhelm
Frew, Ian J
author_facet Albers, Joachim
Rajski, Michal
Schönenberger, Désirée
Harlander, Sabine
Schraml, Peter
von Teichman, Adriana
Georgiev, Strahil
Wild, Peter J
Moch, Holger
Krek, Wilhelm
Frew, Ian J
author_sort Albers, Joachim
collection PubMed
description The combinations of genetic alterations that cooperate with von Hippel–Lindau (VHL) mutation to cause clear cell renal cell carcinoma (ccRCC) remain poorly understood. We show that the TP53 tumour suppressor gene is mutated in approximately 9% of human ccRCCs. Combined deletion of Vhl and Trp53 in primary mouse embryo fibroblasts causes proliferative dysregulation and high rates of aneuploidy. Deletion of these genes in the epithelium of the kidney induces the formation of simple cysts, atypical cysts and neoplasms, and deletion in the epithelia of the genital urinary tract leads to dysplasia and tumour formation. Kidney cysts display a reduced frequency of primary cilia and atypical cysts and neoplasms exhibit a pro-proliferative signature including activation of mTORC1 and high expression of Myc, mimicking several cellular and molecular alterations seen in human ccRCC and its precursor lesions. As the majority of ccRCC is associated with functional inactivation of VHL, our findings suggest that for a subset of ccRCC, loss of p53 function represents a critical event in tumour development.
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spelling pubmed-37794542013-09-23 Combined mutation of Vhl and Trp53 causes renal cysts and tumours in mice Albers, Joachim Rajski, Michal Schönenberger, Désirée Harlander, Sabine Schraml, Peter von Teichman, Adriana Georgiev, Strahil Wild, Peter J Moch, Holger Krek, Wilhelm Frew, Ian J EMBO Mol Med Research Articles The combinations of genetic alterations that cooperate with von Hippel–Lindau (VHL) mutation to cause clear cell renal cell carcinoma (ccRCC) remain poorly understood. We show that the TP53 tumour suppressor gene is mutated in approximately 9% of human ccRCCs. Combined deletion of Vhl and Trp53 in primary mouse embryo fibroblasts causes proliferative dysregulation and high rates of aneuploidy. Deletion of these genes in the epithelium of the kidney induces the formation of simple cysts, atypical cysts and neoplasms, and deletion in the epithelia of the genital urinary tract leads to dysplasia and tumour formation. Kidney cysts display a reduced frequency of primary cilia and atypical cysts and neoplasms exhibit a pro-proliferative signature including activation of mTORC1 and high expression of Myc, mimicking several cellular and molecular alterations seen in human ccRCC and its precursor lesions. As the majority of ccRCC is associated with functional inactivation of VHL, our findings suggest that for a subset of ccRCC, loss of p53 function represents a critical event in tumour development. WILEY-VCH Verlag 2013-06 2013-04-22 /pmc/articles/PMC3779454/ /pubmed/23606570 http://dx.doi.org/10.1002/emmm.201202231 Text en Copyright © 2013 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO http://creativecommons.org/licenses/by/2.5/ Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.5, which does not permit commercial exploitation.
spellingShingle Research Articles
Albers, Joachim
Rajski, Michal
Schönenberger, Désirée
Harlander, Sabine
Schraml, Peter
von Teichman, Adriana
Georgiev, Strahil
Wild, Peter J
Moch, Holger
Krek, Wilhelm
Frew, Ian J
Combined mutation of Vhl and Trp53 causes renal cysts and tumours in mice
title Combined mutation of Vhl and Trp53 causes renal cysts and tumours in mice
title_full Combined mutation of Vhl and Trp53 causes renal cysts and tumours in mice
title_fullStr Combined mutation of Vhl and Trp53 causes renal cysts and tumours in mice
title_full_unstemmed Combined mutation of Vhl and Trp53 causes renal cysts and tumours in mice
title_short Combined mutation of Vhl and Trp53 causes renal cysts and tumours in mice
title_sort combined mutation of vhl and trp53 causes renal cysts and tumours in mice
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3779454/
https://www.ncbi.nlm.nih.gov/pubmed/23606570
http://dx.doi.org/10.1002/emmm.201202231
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