Type 2B von Hippel-Lindau disease: molecular biology, tumor growth, and development Public Deposited

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  • March 22, 2019
  • Lee, Caroline Martz
    • Affiliation: School of Medicine, Curriculum in Genetics and Molecular Biology
  • 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. Interaction analysis in VHL –transgenic murine embryonic stem (ES) and renal cell carcionoma-derived cell lines supported previous observations that VHL Type 2B mutations disrupt the interaction between pVHL and Elongin C but maintain partial regulation of HIF-α, most likely via a remnant complex containing ROC1 and Cullin-2 and reduced or absent Elongin C. Murine embryonic stem (ES) cells in which the endogenous wild-type Vhl gene was replaced with the representative Type 2B VHL hotspot mutation R167Q (Vhl2B/2B) likewise displayed preserved physiologic regulation of both HIF factors with slightly more normoxic dysregulation of HIF-2α. Differentiated Vhl2B/2B-derived teratomas overexpressed the joint HIF targets Vegf and EglN3 but not the HIF-1α-specific target Pfk1 and 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. Vhl2B/2B mice displayed mid-gestational embryonic lethality, while adult Vhl2B/+ mice exhibited susceptibility to carcinogenpromoted renal neoplasia compared with wild-type littermates at twelve months. Our experiments support a model in which the representative Type 2B R167Q mutant pVhl retains intermediate HIF-α suppression via formation of a remnant ubiquitin ligase complex, thereby producing a unique profile of HIF-α dysregulation with tissue-specific effects on cell growth, development, and tumor predisposition.
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  • Rathmell, W. Kimryn
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  • University of North Carolina at Chapel Hill
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