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von Hippel-Lindau disease tumor suppressor; pVHL; protein G7 (VHL)

Function: - role in ubiquitination & subsequent proteasomal degradation via the von Hippel-Lindau ubiquitination complex - seems to act as target recruitment subunit in the E3 ubiquitin ligase complex & recruits hydroxylated hypoxia-inducible factor (HIF) under normoxic conditions - involved in transcriptional repression through interaction with HIF1A, HIF1AN & histone deacetylases - protein modification; protein ubiquitination component of the VCB complex (VHL-elongin B, elongin C-CUL2 complex) - interaction with CUL2 is dependent on integrity of the trimeric VBC complex - interacts (via beta domain) with HIF1A (via NTAD domain); this interaction mediates degradation of HIF1A in normoxia &, in hypoxia, prevents ubiqitination & degradation of HIF1A by mediating hypoxia-induced translocation to the nucleus, a process which requires a hypoxia-dependent regulatory signal - interacts with RNF139 & UBP33 - interacts with PHF17 Structure: - the elongin BC complex binding domain is also known as BC-box with the consensus [APST]-L-x(3)-C-x(3)-[AILV] Compartment: - isoform 1: - cytoplasm, membrane, nucleus - found predominantly in the cytoplasm & with lesser amounts nuclear or membrane-associated - isoform 3 - cytoplasm, nucleus - equally distributed between nucleus & cytoplasm but not membrane-associated Alternative initiation: named isoforms=3 Expression: - expressed in the adult & fetal brain & kidney Pathology: - loss of VHL heterozygosity are a cause of pheochromocytoma - defects in VHL are the cause of a) von Hippel-lindau disease b) erythrocytosis familial type 2 c) renal cell carcinoma type 1 d) some cases of sporadic cerebellar hemangioblastoma - ~70% of mutations affect region involved in elongin binding - VHL associated tumors show upregulation of vascular endothelial growth factor (VEGF) & wild type inhibits VEGF promoter activity Notes: - VHL forms a complex (VCB complex) with elongin C & elongin B - VCB also binds cul2 (cul2 - elongin C association), elongin & suppressor of cytokine signaling family proteins [4]

Interactions

molecular events

Related

von Hippel-Lindau disease von Hippel-Lindau disease tumor suppressor [VHL] gene

General

anti-oncoprotein (tumor suppressor protein)

Properties

SIZE: entity length = 213 aa MW = 24 kD COMPARTMENT: cytoplasm cell nucleus MOTIF: repeat {14-53} MOTIF: consensus repeat {14-18} consensus repeat {19-23} consensus repeat {24-28} consensus repeat {29-33} consensus repeat {34-38} consensus repeat {39-43} consensus repeat {44-48} consensus repeat {49-53} domain {100-155} domain {157-166}

References

  1. OMIM :accession 193300
  2. UniProt :accession P40337
  3. Iliopoulos O et al. Tumour suppression by the human von Hippel-Lindau gene product. Nature Med 1:822-6 1995 PMID: 7585187
  4. Stebbins CE et al. Structure of the VHL-ElonginC-ElonginB complex: implications for VHL tumor suppressor function. Science 284:455-61, 1999 PMID: 10205047
  5. Entrez Gene :accession 7428
  6. Atlas of Genetics & Cytogenetics in Oncology & Haematology http://atlasgeneticsoncology.org/genes/VHLID132.html
  7. GeneReviews https://www.genecards.org/cgi-bin/carddisp.pl?gene=VHL

Component-of

molecular complex

Databases & Figures

OMIM correlations MORBIDMAP 608537 UniProt P40337 Pfam PF01847 Entrez Gene 7428 Kegg hsa:7428 HIF-1 pathway