Human Molecular Genetics, 2001, Vol. 10, No. 10 1029-1038
© 2001 Oxford University Press
Contrasting effects on HIF-1
regulation by disease-causing pVHL mutations correlate with patterns of tumourigenesis in von Hippel-Lindau disease
1Section of Medical and Molecular Genetics, Department of Paediatrics and Child Health, University of Birmingham, The Medical School, Edgbaston, Birmingham B15 2TT, UK, 2Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK and 3Cambridge University Department of Pathology, Tennis Court Road, Cambridge CB1 4QP, UK
The von Hippel-Lindau tumour suppressor gene product (pVHL) associates with the elongin B and C and Cul2 proteins to form a ubiquitin-ligase complex (VCBC). To date, the only VCBC substrates identified are the hypoxia-inducible factor 
subunits (HIF-1 and HIF-2). However, pVHL is thought to have multiple functions and the significance of HIF-1 and HIF-2 regulation for tumour suppressor activity has not been defined. VHL disease is characterized by distinct clinical subtypes. Thus haemangioblastomas (HABs) and renal cell carcinoma (RCC) but not phaeochromocytoma (PHE) occur in type 1 VHL disease. Type 2 subtypes are characterized by PHE susceptibility but differ with respect to additional tumours (type 2A, PHE+HAB but not RCC; type 2B, PHE+ HAB+RCC; type 2C, PHE only). We investigated in detail the effect of 13 naturally occurring VHL mutations (11 missense), representing each phenotypic subclass, on HIF- subunit regulation. Consistent effects on pVHL function were observed for all mutations within each subclass. Mutations associated with the PHE-only phenotype (type 2C) promoted HIF- ubiquitylation in vitro and demonstrated wild-type binding patterns with pVHL interacting proteins, suggesting that loss of other pVHL functions are necessary for PHE susceptibility. Mutations causing HAB susceptibility (types 1, 2A and 2B) demonstrated variable effects on HIF- subunit and elongin binding, but all resulted in defective HIF- regulation and loss of p220 (fibronectin) binding. All RCC-associated mutations caused complete HIF- dysregulation and loss of p220 (fibronectin) binding. Our findings are consistent with impaired ability to degrade HIF- subunit being required for HAB development and RCC susceptibility.
+ Present address: Cancer Research Unit, University of Newcastle, Newcastle-upon-Tyne NE2 4HH, UK
Present address: Department of Medicine, Hammersmith Hospital, London W12, UK
¶ To whom correspondence should be addressed. Tel: +44 121 627 2741; Fax: +44 121 414 2538; Email: e.r.maher@bham.ac.uk
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