Daam2 driven degradation of VHL promotes gliomagenesis

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

doi:10.7554/eLife.31926

Daam2 driven degradation of VHL promotes gliomagenesis

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

Neuroscience

Research output: Contribution to journal › Article › peer-review

16 Scopus citations

Abstract

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.

Original language	English (US)
Article number	e31926
Journal	eLife
Volume	6
DOIs	https://doi.org/10.7554/eLife.31926
State	Published - Oct 20 2017

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)
Immunology and Microbiology(all)
Neuroscience(all)

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10.7554/eLife.31926

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title = "Daam2 driven degradation of VHL promotes gliomagenesis",

abstract = "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.",

author = "Wenyi Zhu and Saritha Krishna and Cristina Garcia and Lin, {Chia Ching John} and Mitchell, {Bartley D.} and Scott, {Kenneth L.} and Mohila, {Carrie A.} and Creighton, {Chad J.} and Yoo, {Seung Hee} and Lee, {Hyun Kyoung} and Benjamin Deneen",

note = "Funding Information: This work was supported by grants from the Sontag Foundation (BD), Cancer Prevention Research Institute of Texas (RP150334 and RP160192 to BD and CC), and the National Institutes of Health (NS071153 and NS089366 to BD). National Multiple Sclerosis Scoiety (RG 1508-08406 to HKL). We acknowledge the assistance of the Baylor College of Medicine Mouse Phenotyping Core, the Lester and Sue Smith Breast Center{\textquoteright}s Pathology Core, and Functional Proteomics RPPA Core Facility at MD Anderson Cancer Center, this facility is funded by NCI # CA16672. This project was also supported in part by the IDDRC grant number 1U54 HD083092 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Publisher Copyright: {\textcopyright} Zhu et al.",

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AU - Zhu, Wenyi

AU - Krishna, Saritha

AU - Garcia, Cristina

AU - Lin, Chia Ching John

AU - Mitchell, Bartley D.

AU - Scott, Kenneth L.

AU - Mohila, Carrie A.

AU - Creighton, Chad J.

AU - Yoo, Seung Hee

AU - Lee, Hyun Kyoung

AU - Deneen, Benjamin

N1 - Funding Information: This work was supported by grants from the Sontag Foundation (BD), Cancer Prevention Research Institute of Texas (RP150334 and RP160192 to BD and CC), and the National Institutes of Health (NS071153 and NS089366 to BD). National Multiple Sclerosis Scoiety (RG 1508-08406 to HKL). We acknowledge the assistance of the Baylor College of Medicine Mouse Phenotyping Core, the Lester and Sue Smith Breast Center’s Pathology Core, and Functional Proteomics RPPA Core Facility at MD Anderson Cancer Center, this facility is funded by NCI # CA16672. This project was also supported in part by the IDDRC grant number 1U54 HD083092 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Publisher Copyright: © Zhu et al.

PY - 2017/10/20

Y1 - 2017/10/20

N2 - 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.

AB - 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.

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Daam2 driven degradation of VHL promotes gliomagenesis

Abstract

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