VHL Type 2B gene mutation moderates HIF dosage in vitro and in vivo

C. M. Lee; M. M. Hickey; C. A. Sanford; C. G. McGuire; C. L. Cowey; M. C. Simon; W. K. Rathmell

doi:10.1038/onc.2009.12

VHL Type 2B gene mutation moderates HIF dosage in vitro and in vivo

C. M. Lee, M. M. Hickey, C. A. Sanford, C. G. McGuire, C. L. Cowey, M. C. Simon, W. K. Rathmell

Division of Hospital Medicine

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

35 Scopus citations

Abstract

Von Hippel-Lindau (VHL) disease is caused by germline mutations in the VHL tumor suppressor gene, with Type 2B missense VHL mutations predisposing to renal cell carcinoma, hemangioblastoma and pheochromocytoma. Type 2B mutant pVHL is predicted to be defective in hypoxia inducible factor (HIF)-α regulation. Murine embryonic stem (ES) cells in which the endogenous wild-type Vhl gene was replaced with the representative Type 2B VHL hotspot mutation R167Q (Vhl 2B/2B) displayed preserved physiological regulation of both HIF factors with slightly greater normoxic dysregulation of HIF-2α. Differentiated Vhl 2B/2B -derived teratomas overexpressed joint HIF targets Vegf and EglN3 but not the HIF-1α-specific target Pfk1. Vhl 2B/2B teratomas additionally displayed a growth advantage over Vhl / -derived teratomas, suggestive of a tight connection between perturbations in the degree and ratio of HIF-1α and HIF-2α stabilization and cell growth. Vhl 2B/2B mice displayed mid-gestational embryonic lethality, whereas adult Vhl 2B/ mice exhibited susceptibility to carcinogen-promoted renal neoplasia compared with wild-type littermates at 12 months. Our experiments support a model in which the representative Type 2B R167Q mutant pVhl produces a unique profile of HIF dysregulation, thereby promoting tissue-specific effects on cell growth, development and tumor predisposition.

Original language	English
Pages (from-to)	1694-1705
Number of pages	12
Journal	Oncogene
Volume	28
Issue number	14
DOIs	https://doi.org/10.1038/onc.2009.12
State	Published - Apr 9 2009

Keywords

Hypoxia inducible factors
Renal cell carcinoma
Von HippelLindau

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10.1038/onc.2009.12

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@article{0c97782a2b7c4904b15ce1bc24086123,

title = "VHL Type 2B gene mutation moderates HIF dosage in vitro and in vivo",

abstract = "Von Hippel-Lindau (VHL) disease is caused by germline mutations in the VHL tumor suppressor gene, with Type 2B missense VHL mutations predisposing to renal cell carcinoma, hemangioblastoma and pheochromocytoma. Type 2B mutant pVHL is predicted to be defective in hypoxia inducible factor (HIF)-α regulation. Murine embryonic stem (ES) cells in which the endogenous wild-type Vhl gene was replaced with the representative Type 2B VHL hotspot mutation R167Q (Vhl 2B/2B) displayed preserved physiological regulation of both HIF factors with slightly greater normoxic dysregulation of HIF-2α. Differentiated Vhl 2B/2B -derived teratomas overexpressed joint HIF targets Vegf and EglN3 but not the HIF-1α-specific target Pfk1. Vhl 2B/2B teratomas additionally displayed a growth advantage over Vhl / -derived teratomas, suggestive of a tight connection between perturbations in the degree and ratio of HIF-1α and HIF-2α stabilization and cell growth. Vhl 2B/2B mice displayed mid-gestational embryonic lethality, whereas adult Vhl 2B/ mice exhibited susceptibility to carcinogen-promoted renal neoplasia compared with wild-type littermates at 12 months. Our experiments support a model in which the representative Type 2B R167Q mutant pVhl produces a unique profile of HIF dysregulation, thereby promoting tissue-specific effects on cell growth, development and tumor predisposition.",

keywords = "Hypoxia inducible factors, Renal cell carcinoma, Von HippelLindau",

author = "Lee, {C. M.} and Hickey, {M. M.} and Sanford, {C. A.} and McGuire, {C. G.} and Cowey, {C. L.} and Simon, {M. C.} and Rathmell, {W. K.}",

note = "Funding Information: We thank Dr T Van Dyke and members of her laboratory, Dr I Davis, and Dr WY Kim for many helpful discussions. This work was supported by the V Foundation, the American Cancer Society, the VHL Family Alliance, and the NCI K08098410 and R01121781 (WKR); by the Howard Hughes Medical Institute (MCS, MMH); and by the NIEHS F30015248 (CML).",

year = "2009",

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doi = "10.1038/onc.2009.12",

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AU - Lee, C. M.

AU - Hickey, M. M.

AU - Sanford, C. A.

AU - McGuire, C. G.

AU - Cowey, C. L.

AU - Simon, M. C.

AU - Rathmell, W. K.

N1 - Funding Information: We thank Dr T Van Dyke and members of her laboratory, Dr I Davis, and Dr WY Kim for many helpful discussions. This work was supported by the V Foundation, the American Cancer Society, the VHL Family Alliance, and the NCI K08098410 and R01121781 (WKR); by the Howard Hughes Medical Institute (MCS, MMH); and by the NIEHS F30015248 (CML).

PY - 2009/4/9

Y1 - 2009/4/9

N2 - Von Hippel-Lindau (VHL) disease is caused by germline mutations in the VHL tumor suppressor gene, with Type 2B missense VHL mutations predisposing to renal cell carcinoma, hemangioblastoma and pheochromocytoma. Type 2B mutant pVHL is predicted to be defective in hypoxia inducible factor (HIF)-α regulation. Murine embryonic stem (ES) cells in which the endogenous wild-type Vhl gene was replaced with the representative Type 2B VHL hotspot mutation R167Q (Vhl 2B/2B) displayed preserved physiological regulation of both HIF factors with slightly greater normoxic dysregulation of HIF-2α. Differentiated Vhl 2B/2B -derived teratomas overexpressed joint HIF targets Vegf and EglN3 but not the HIF-1α-specific target Pfk1. Vhl 2B/2B teratomas additionally displayed a growth advantage over Vhl / -derived teratomas, suggestive of a tight connection between perturbations in the degree and ratio of HIF-1α and HIF-2α stabilization and cell growth. Vhl 2B/2B mice displayed mid-gestational embryonic lethality, whereas adult Vhl 2B/ mice exhibited susceptibility to carcinogen-promoted renal neoplasia compared with wild-type littermates at 12 months. Our experiments support a model in which the representative Type 2B R167Q mutant pVhl produces a unique profile of HIF dysregulation, thereby promoting tissue-specific effects on cell growth, development and tumor predisposition.

AB - Von Hippel-Lindau (VHL) disease is caused by germline mutations in the VHL tumor suppressor gene, with Type 2B missense VHL mutations predisposing to renal cell carcinoma, hemangioblastoma and pheochromocytoma. Type 2B mutant pVHL is predicted to be defective in hypoxia inducible factor (HIF)-α regulation. Murine embryonic stem (ES) cells in which the endogenous wild-type Vhl gene was replaced with the representative Type 2B VHL hotspot mutation R167Q (Vhl 2B/2B) displayed preserved physiological regulation of both HIF factors with slightly greater normoxic dysregulation of HIF-2α. Differentiated Vhl 2B/2B -derived teratomas overexpressed joint HIF targets Vegf and EglN3 but not the HIF-1α-specific target Pfk1. Vhl 2B/2B teratomas additionally displayed a growth advantage over Vhl / -derived teratomas, suggestive of a tight connection between perturbations in the degree and ratio of HIF-1α and HIF-2α stabilization and cell growth. Vhl 2B/2B mice displayed mid-gestational embryonic lethality, whereas adult Vhl 2B/ mice exhibited susceptibility to carcinogen-promoted renal neoplasia compared with wild-type littermates at 12 months. Our experiments support a model in which the representative Type 2B R167Q mutant pVhl produces a unique profile of HIF dysregulation, thereby promoting tissue-specific effects on cell growth, development and tumor predisposition.

KW - Hypoxia inducible factors

KW - Renal cell carcinoma

KW - Von HippelLindau

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DO - 10.1038/onc.2009.12

M3 - Article

C2 - 19252526

AN - SCOPUS:64949107042

SN - 0950-9232

VL - 28

SP - 1694

EP - 1705

JO - Oncogene

JF - Oncogene

IS - 14

ER -

VHL Type 2B gene mutation moderates HIF dosage in vitro and in vivo

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