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Cancer Gene and Genomics

Molecular Cloning and Characterization of the von Hippel-Lindau-Like Protein¹

¹ Department of Laboratory Medicine and Pathobiology and
² Department of Obstetrics and Gynecology, University of Toronto, Toronto, Ontario, Canada; and
³ Department of Molecular Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA

Requests for reprints: Michael Ohh, Department of Laboratory Medicine and Pathobiology, University of Toronto, 1 King's College Circle, Toronto, Ontario, M5S 1A8 Canada. Phone: (416) 946-7922; Fax: (416) 978-5959. E-mail: michael.ohh{at}utoronto.ca

von Hippel-Lindau (VHL) tumor suppressor protein—inactivated in VHL disease and sporadic kidney cancer—is a component of an E3 ubiquitin ligase complex that selectively ubiquitinates the subunit of the hypoxia-inducible factor (HIF) transcription factor for subsequent destruction by the 26S proteasome. Here, we report the identification and characterization of the first VHL homologue, VHL-like protein (VLP), located on chromosome 1q21.2. A 676-bp partial cDNA encoding a 139-amino acid protein that is 78% similar to VHL was isolated by reverse transcription-PCR from human brain cerebellum and several cancer cell lines. The expression of VLP transcript is most abundant in the placenta. Like VHL, VLP contains a ß domain capable of binding HIF. However, unlike VHL, it does not contain a recognizable domain, which is required for nucleating the multiprotein E3 ubiquitin ligase complex. The increased expression of VLP in the presence of VHL attenuated the ubiquitination of HIF and led to the accumulation of downstream HIF target genes. These results taken together indicate that VLP functions as a dominant-negative VHL to serve as a protector of HIF.

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