von Hippel-Lindau Disease Monica Gonzalez

VHL Disease Overview Abnormal blood vessel growth Dominantly inherited 1 in 36,000 births Cancer develops in CNS, eyes, adrenal glands, kidneys… CHB: cerebellar haemangioblastoma; brain tumor RET: retinal angioma; eye tumor RCC: renal cell carcinoma; kidney tumor

VHL is a Tumor Suppressor

VHL is a Tumor Suppressor

VHL Gene and Protein The VHL gene consists of three exons encoding a 4.7 kb mRNA. Location: chromosome 3p25-p26. It encodes a polypeptide of 213 amino acids from the first methionine codon, and a protein of 160 aa from a second methionine at codon 54. Both MET appear to be used as start codons. There is also alternative splicing: a small proportion of VHL mRNA lacks exon 2 (isoform 2; see later), which is predicted to produce an in-frame deletion of 41 amino acids, if translated. The VHL gene sequence is highly conserved in primates and rodents, and has homologues in C. elegans and Drosophila melanogaster. Sequence conservation is poor before codon 54 (the second methionine), and this repeat is not present in the rodent VHL genes, so the functional significance of this region is unclear. No mutations have been detected in codons 1 to 54 (i.e. before the second methionine start codon), suggesting that the regions is not required for tumour suppressor function.

VHL Gene and Protein

pVHL Function (a) Wild-type pVHL under normal oxygen (normoxic) conditions binds via its a-domain to elongin C and forms a complex with elongin B and CUL2. Assisted by Rbx1 and possibly NEDD8, this complex acts as an E3 ubiquitin ligase, transferring ubiquitin from the E2 ubiquitin-conjugating enzyme onto the substrate, the HIF-1a transcription factor, which is bound to the b-domain of pVHL. Ubiquitinated HIF-1a is then targeted for degradation by the proteasome.

pVHL Function (b) pVHL with a mutation in the b-domain is unable to bind to HIF-1a, which does not become ubiquitinated and is not degraded. Elevated levels of HIF-1a protein then activate transcription of target genes that are normally induced only by hypoxia, including VEGF, which might play a role in development of the vascular tumours of VHL disease.

pVHL Function (c) pVHL with a mutation in the a-domain is unable to bind to elongin C, so the E3 ubiquitin ligase complex does not form and is unable to ubiquitinate HIF-1a. HIF-1a levels increase and transcription of target genes is induced. Abbreviations: CUL2, cullin 2; E2, E2 ubiquitin-conjugating enzyme (e.g. Ubc5a); GLUT-1, glucose transporter 1; HIF-1a, hypoxia-inducible transcription factor 1a; PDGF-B, platelet-derived growth factor B chain; Ub, ubiquitin; VCB complex, trimeric complex of pVHL, elongin C and elongin B; VEGF, vascular endothelial growth factor (fig005frb).

Knockout Mice Homozygous Vhl −/− is embryonic lethal, as a result of defective placental vasculogenesis. Heterozygous Vhl +/− appear normal.

pVHL Targets

Summary Disease is a multiple-cancer syndrome Tumor suppressor E3 Ubiquitin Ligase Complex Downregulates HIF-1α (hypoxia response)