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      von Hippel-Lindau Tumor Suppressor Protein and Hypoxia-Inducible Factor in Kidney Cancer

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          Abstract

          The development of hereditary von Hippel-Lindau (VHL) disease and the majority of sporadic kidney cancers are due to the functional inactivation of the VHL gene. The product of the VHL gene, pVHL, in association with elongins B and C, cullin 2, and Rbx1 form an E3 ubiquitin-ligase complex VEC that targets the alpha subunits of hypoxia-inducible factor (HIF) for ubiquitination. Ubiquitin-tagged HIF-α proteins are subsequently degraded by the common 26S proteasome. pVHL functions as the substrate-docking interface that specifically recognizes prolyl-hydroxylated HIF-α. This hydroxylation occurs only in the presence of oxygen or normoxia. Thus, under hypoxia, HIF-α subunits are no longer subjected to degradation and are thereby able to dimerize with the common and constitutively stable β subunits. The heterodimeric HIFs upregulate a myriad of hypoxia-inducible genes, triggering our physiologic response to hypoxia. Inappropriate accumulations of HIF-α in VHL disease are believed to contribute to the pathogenesis via the upregulation of several of these HIF target genes. Our current molecular understanding of the roles of HIF and pVHL in the development of VHL-associated clear-cell renal cell carcinoma (CC-RCC) is the focus of this review.

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          Most cited references 66

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          Mutations of the VHL tumour suppressor gene in renal carcinoma.

          Multiple, bilateral renal carcinomas are a frequent occurrence in von Hippel-Lindau (VHL) disease. To elucidate the aetiological role of the VHL gene in human kidney tumorigenesis, localized and advanced tumours from 110 patients with sporadic renal carcinoma were analysed for VHL mutations and loss of heterozygosity (LOH). VHL mutations were identified in 57% of clear cell renal carcinomas analysed and LOH was observed in 98% of those samples. Moreover, VHL was mutated and lost in a renal tumour from a patient with familial renal carcinoma carrying the constitutional translocation, t(3;8)(p14;q24). The identification of VHL mutations in a majority of localized and advanced sporadic renal carcinomas and in a second form of hereditary renal carcinoma indicates that the VHL gene plays a critical part in the origin of this malignancy.
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            Ubiquitination of hypoxia-inducible factor requires direct binding to the beta-domain of the von Hippel-Lindau protein.

            von Hippel-Lindau (VHL) disease is a hereditary cancer syndrome that is characterized by the development of multiple vascular tumors and is caused by inactivation of the von Hippel-Lindau protein (pVHL). Here we show that pVHL, through its beta-domain, binds directly to hypoxia-inducible factor (HIF), thereby targeting HIF for ubiquitination in an alpha-domain-dependent manner. This is the first function to be ascribed to the pVHL beta-domain. Furthermore, we provide the first direct evidence that pVHL has a function analogous to that of an F-box protein, namely, to recruit substrates to a ubiquitination machine. These results strengthen the link between overaccumulation of HIF and development of VHL disease.
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              SKP1 connects cell cycle regulators to the ubiquitin proteolysis machinery through a novel motif, the F-box.

              We have identified the yeast and human homologs of the SKP1 gene as a suppressor of cdc4 mutants and as a cyclin F-binding protein. Skp1p indirectly binds cyclin A/Cdk2 through Skp2p, and directly binds Skp2p, cyclin F, and Cdc4p through a novel structural motif called the F-box. SKP1 is required for ubiquitin-mediated proteolysis of Cin2p, Clb5p, and the Cdk inhibitor Sic1p, and provides a link between these molecules and the proteolysis machinery. A large number of proteins contain the F-box motif and are thereby implicated in the ubiquitin pathway. Different skp1 mutants arrest cells in either G1 or G2, suggesting a connection between regulation of proteolysis in different stages of the cycle.
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                Author and article information

                Journal
                AJN
                Am J Nephrol
                10.1159/issn.0250-8095
                American Journal of Nephrology
                S. Karger AG
                0250-8095
                1421-9670
                2004
                February 2004
                16 February 2004
                : 24
                : 1
                : 1-13
                Affiliations
                Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, Ont., Canada
                Article
                75346 Am J Nephrol 2004;24:1–13
                10.1159/000075346
                14654728
                © 2004 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 2, Tables: 1, References: 152, Pages: 13
                Product
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/75346
                Categories
                In-Depth Topic Review

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