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 alpha 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 beta domain capable of binding HIFalpha. However, unlike VHL, it does not contain a recognizable alpha 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 HIFalpha 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 HIFalpha.
A reference proteome is a set of protein sequences derived from a complete proteome which constitutes a defined standard for a particular user community. Reference proteomes are manually defined according to a number of criteria. They cover the proteomes of well- studied model organisms and other proteomes of interest for biomedical and biotechnological research. Reference proteomes have been selected to provide broad coverage of the tree of life, and constitute a representative cross-section of the taxonomic diversity to be found within UniProtKB.
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