NEDD8 modification of the von Hippel-Lindau protein in tumour development.
Published: 2004
Language: eng
Number of pages: 109
Description: Functional inactivation of the von Hippel-Lindau (VHL) tumour suppressor gene is the cause of the familial VHL disease and most of sporadic renal clear cell carcinomas (RCC). 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 fibronectin matrix, underscoring its potential importance in VHL disease. Here, we report that an ubiquitin-like molecule called NEDD8 covalently modifies pVHL. A non-neddylateable pVHL mutant, while retaining its ability to ubiquitylate HIF, failed to bind and promote the assembly of fibronectin matrix. Expression of the neddylation-defective pVHL in RCC cells was insufficient to suppress the formation of tumours in SCID mice. The results suggest that NEDD8 modification of pVHL plays an important role in fibronectin matrix assembly and in the absence of such regulation, an intact HIF-pathway is insufficient to prevent VHL-associated tumourigenesis.
Notes: Adviser:  Michael Ohh.

Thesis (M.Sc.)--University of Toronto, 2004.

Electronic version licensed for access by U. of T. users.

Source: Masters Abstracts International, Volume: 43-03, page: 0788.

MICR copy on microfiche (2 microfiches).