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Molecular and Cellular Biology, April 2004, p. 3251-3261, Vol. 24, No. 8
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.8.3251-3261.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

pVHL Modification by NEDD8 Is Required for Fibronectin Matrix Assembly and Suppression of Tumor Development

Natalie H. Stickle,1 Jacky Chung,1 Jeffery M. Klco,2 Richard P. Hill,3 William G. Kaelin Jr.,4 and Michael Ohh1*

Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8,1 Department of Medical Biophysics, University of Toronto and Ontario Cancer Institute, Princess Margaret Hospital, Toronto, Ontario M5G 2M9, Canada,3 Washington University School of Medicine, St. Louis, Missouri 63110,2 Department of Molecular Oncology, Dana-Farber Cancer Institute, Harvard Medical School, and Howard Hughes Medical Institute, Boston, Massachusetts 021154

Received 25 June 2003/ Returned for modification 13 August 2003/ Accepted 8 January 2004

Functional inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene is the cause of the familial VHL disease and most sporadic renal clear-cell carcinomas (RCC). pVHL has been shown to play a role in the destruction of hypoxia-inducible factor {alpha} (HIF-{alpha}) subunits via ubiquitin-mediated proteolysis and in the regulation of fibronectin matrix assembly. Although most disease-causing pVHL mutations hinder the regulation of the HIF pathway, every disease-causing pVHL mutant tested to date has failed to promote the assembly of the fibronectin matrix, underscoring its potential importance in VHL disease. Here, we report that a ubiquitin-like molecule called NEDD8 covalently modifies pVHL. A nonneddylateable pVHL mutant, while retaining its ability to ubiquitylate HIF, failed to bind to and promote the assembly of the fibronectin matrix. Expression of the neddylation-defective pVHL in RCC cells, while restoring the regulation of HIF, failed to promote the differentiated morphology in a three-dimensional growth assay and was insufficient to suppress the formation of tumors in SCID mice. These results suggest that NEDD8 modification of pVHL plays an important role in fibronectin matrix assembly and that in the absence of such regulation, an intact HIF pathway is insufficient to prevent VHL-associated tumorigenesis.

* Corresponding author. Mailing address: Department of Laboratory Medicine and Pathobiology, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada. Phone: (416) 946-7922. Fax: (416) 978-5959. E-mail: michael.ohh{at}utoronto.ca.

Molecular and Cellular Biology, April 2004, p. 3251-3261, Vol. 24, No. 8
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.8.3251-3261.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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