Daam2 driven degradation of VHL promotes gliomagenesis
Von Hippel-Landau (VHL) protein is a potent tumor suppressor regulating numerous pathways that drive cancer, but mutations in VHL are restricted to limited subsets of malignancies. Here we identified a novel mechanism for VHL suppression in tumors that do not have inactivating mutations. Using devel...
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doaj-c896bbde90e74bc3b56a52f6fdc76b392021-05-05T13:52:51ZengeLife Sciences Publications LtdeLife2050-084X2017-10-01610.7554/eLife.31926Daam2 driven degradation of VHL promotes gliomagenesisWenyi Zhu0Saritha Krishna1Cristina Garcia2Chia-Ching John Lin3Bartley D Mitchell4Kenneth L Scott5Carrie A Mohila6Chad J Creighton7Seung-Hee Yoo8Hyun Kyoung Lee9Benjamin Deneen10https://orcid.org/0000-0002-6335-1081Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, United States; The Integrative Molecular and Biomedical Sciences Graduate Program, Baylor College of Medicine, Houston, United StatesCenter for Cell and Gene Therapy, Baylor College of Medicine, Houston, United StatesCenter for Cell and Gene Therapy, Baylor College of Medicine, Houston, United StatesCenter for Cell and Gene Therapy, Baylor College of Medicine, Houston, United StatesDepartment of Neurosurgery, Baylor College of Medicine, Houston, United StatesDepartment of Human and Molecular Genetics, Baylor College of Medicine, Houston, United StatesDepartment of Pathology, Texas Children’s Hospital, Houston, United StatesDan L Duncan Cancer Center, Division of Biostatistics, Baylor College of Medicine, Houston, United States; Department of Medicine, Baylor College of Medicine, Houston, United StatesDepartment of Biochemistry and Molecular Biology, The University of Texas Heath Science Center at Houston, Houston, United StatesDepartment of Pediatrics, Division of Neurology, Baylor College of Medicine, Houston, United States; Neurological Research Institute, Texas Children’s Hospital, Houston, United States; Department of Neuroscience, Baylor College of Medicine, Houston, United StatesCenter for Cell and Gene Therapy, Baylor College of Medicine, Houston, United States; The Integrative Molecular and Biomedical Sciences Graduate Program, Baylor College of Medicine, Houston, United States; Neurological Research Institute, Texas Children’s Hospital, Houston, United States; Department of Neuroscience, Baylor College of Medicine, Houston, United StatesVon Hippel-Landau (VHL) protein is a potent tumor suppressor regulating numerous pathways that drive cancer, but mutations in VHL are restricted to limited subsets of malignancies. Here we identified a novel mechanism for VHL suppression in tumors that do not have inactivating mutations. Using developmental processes to uncover new pathways contributing to tumorigenesis, we found that Daam2 promotes glioma formation. Protein expression screening identified an inverse correlation between Daam2 and VHL expression across a host of cancers, including glioma. These in silico insights guided corroborating functional studies, which revealed that Daam2 promotes tumorigenesis by suppressing VHL expression. Furthermore, biochemical analyses demonstrate that Daam2 associates with VHL and facilitates its ubiquitination and degradation. Together, these studies are the first to define an upstream mechanism regulating VHL suppression in cancer and describe the role of Daam2 in tumorigenesis.https://elifesciences.org/articles/31926Cancer BiologyHumanMouse |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Wenyi Zhu Saritha Krishna Cristina Garcia Chia-Ching John Lin Bartley D Mitchell Kenneth L Scott Carrie A Mohila Chad J Creighton Seung-Hee Yoo Hyun Kyoung Lee Benjamin Deneen |
spellingShingle |
Wenyi Zhu Saritha Krishna Cristina Garcia Chia-Ching John Lin Bartley D Mitchell Kenneth L Scott Carrie A Mohila Chad J Creighton Seung-Hee Yoo Hyun Kyoung Lee Benjamin Deneen Daam2 driven degradation of VHL promotes gliomagenesis eLife Cancer Biology Human Mouse |
author_facet |
Wenyi Zhu Saritha Krishna Cristina Garcia Chia-Ching John Lin Bartley D Mitchell Kenneth L Scott Carrie A Mohila Chad J Creighton Seung-Hee Yoo Hyun Kyoung Lee Benjamin Deneen |
author_sort |
Wenyi Zhu |
title |
Daam2 driven degradation of VHL promotes gliomagenesis |
title_short |
Daam2 driven degradation of VHL promotes gliomagenesis |
title_full |
Daam2 driven degradation of VHL promotes gliomagenesis |
title_fullStr |
Daam2 driven degradation of VHL promotes gliomagenesis |
title_full_unstemmed |
Daam2 driven degradation of VHL promotes gliomagenesis |
title_sort |
daam2 driven degradation of vhl promotes gliomagenesis |
publisher |
eLife Sciences Publications Ltd |
series |
eLife |
issn |
2050-084X |
publishDate |
2017-10-01 |
description |
Von Hippel-Landau (VHL) protein is a potent tumor suppressor regulating numerous pathways that drive cancer, but mutations in VHL are restricted to limited subsets of malignancies. Here we identified a novel mechanism for VHL suppression in tumors that do not have inactivating mutations. Using developmental processes to uncover new pathways contributing to tumorigenesis, we found that Daam2 promotes glioma formation. Protein expression screening identified an inverse correlation between Daam2 and VHL expression across a host of cancers, including glioma. These in silico insights guided corroborating functional studies, which revealed that Daam2 promotes tumorigenesis by suppressing VHL expression. Furthermore, biochemical analyses demonstrate that Daam2 associates with VHL and facilitates its ubiquitination and degradation. Together, these studies are the first to define an upstream mechanism regulating VHL suppression in cancer and describe the role of Daam2 in tumorigenesis. |
topic |
Cancer Biology Human Mouse |
url |
https://elifesciences.org/articles/31926 |
work_keys_str_mv |
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