VHL (von Hippel-Lindau tumor suppressor)

Description	The VHL gene spans 10 kb and is composed of three exons.
Transcription	The VHL gene encodes a 4.7 kb mRNA which is widely expressed in both foetal and adult tissues. An alternatively spliced VHL transcript has been detected reflecting the absence of exon 2 (isoform II) but no endogenous associated protein has been reported.

Description	The full-length VHL protein, pVHL, contains 213 amino-acids (28-30 kDa) ("pVHL30") A second major VHL-gene product arises by internal translation initiation from the codon 54 methionine, producing a 160 amino-acid protein (18-19 kDa) ("pVHL19").
Expression	pVHL is widely expressed in both foetal and adult human tissues.
Localisation	The pVHL is largely a cytoplasmic protein but appears to shuttle between the cytoplasm and nucleus.
Function	pVHL interacts with three other proteins, elongin C and B and Cullin 2 (CUL2), in a complex referred to as VCB-CUL2. pVHL has two main structural domains: an N-terminal domain composed mainly of b-sheets (the b domain) and a smaller C-terminal domain between aminoacids 155-192 composed mainly of a helices (a-domain). The a domain consists of three a helices that combines with a fourth a helice donated by elongin C. The b-domain is on the opposite side of the a domain and is free to contact other protein. VHL and angiogenesis A main function of the pVHL is to negatively regulate hypoxia-inducible mRNAs such as the mRNA encoding VEGF, EPO, PDGF and the glucose-transporter GLUT-1. pVHL plays a critical role in targeting the hypoxia-inducible transcription factor HIF-1a for degradation by the proteasome. HIF-1a contribute to form the HIF-1 transcriptional complex responsible for activation of genes involved in metabolism, angiogenesis and apoptosis. The VCB-CUL2 complex has been demonstrated as a ubiquitin-ligase system presenting many similarities with the SCF system ("Skp1-CUL1-Fbox protein"). HIF is normally degraded under normoxic conditions and binding to VHL is dependent on hydroxylation of Pro 564 in HIF-1a (Figure 1). When the VHL gene is mutated, absence of HIF degradation is responsible for abnormal accumulation of VEGF and other hypoxia-inducible mRNA explaining the angiogenic phenotype of VHL tumours. pVHL may also downregulate VEGF production by direct binding and inhibiting to the transcriptional activator SP1. In homozygous VHL knock-out mice, embryos will die early because of a major disorder of placental vasculogenesis . Other functions pVHL plays a role in 1- ability of cells to exit the cell cycle and enter the quiescent state. 2- assembly of extracellular fibronectin matrix. 3- degradation of TGFa LYT10, TGFb, and carbonic anhydrases CA9 and CA12. 4- regulation of the urokinase-type plasminogen activator system. 5- inhibition of the hepatocyte growth factor-induced invasion in renal cell carcinoma. 6- a direct interaction with atypical protein kinase C (PKC) z and l has also recently been demonstrated. Thus, VHL appears as a multifunctional gene and may play a gatekeeper role specially in kidney.
Homology	The primary sequence structure of pVHL shows minimal homology to any know protein but evolutionary conservation of the pVHL is very strong except for the first 53 amino acids.

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