Von Hippel–Lindau tumor suppressor

4WQO, 1LM8, 1LQB, 1VCB, 3ZRC, 3ZRF, 3ZTC, 3ZTD, 3ZUN, 4AJY, 4AWJ, 4B95, 4B9K, 4BKS, 4BKT, 4W9C, 4W9D, 4W9E, 4W9F, 4W9G, 4W9H, 4W9I, 4W9J, 4W9K, 4W9L742822346ENSG00000134086ENSMUSG00000033933P40337P40338NM_000551NM_198156NM_001354723NM_009507NP_000542NP_937799NP_001341652NP_000542.1NP_033533The Von Hippel–Lindau tumor suppressor also known as pVHL is a protein that, in humans, is encoded by the VHL gene.

Mutations of the VHL gene are associated with Von Hippel–Lindau disease, which is characterized by hemangioblastomas of the brain, spinal cord and retina.

[7] HIFs are necessary for tumor growth because most cancers demand high metabolic activity and are only supplied by structurally or functionally inadequate vasculature.

Firstly, all renal cell carcinoma mutations in VHL that have been tested affect the protein's ability to modify HIF.

Additionally, HIF activation can be detected in the earliest events in tumorigenesis in patients with VHL syndrome.

This indicates that the HIF transcription factor distribution in kidney cancer is of major importance in determining the outcome of the patients.

[9] In the normal cell with active VHL protein, HIF alpha is regulated by hydroxylation in the presence of oxygen.

Hydroxylation of HIF creates a binding site for pVHL (the protein product of the VHL gene).

Cells with abnormal pVHL are unable to disrupt the formation of these dimers, and therefore behave like they are hypoxic even in oxygenated environments.

This theory has been disproved multiple times since in all cell types loss of VHL function leads to constitutive activation of HIF and its downstream effects.

Additionally, the nature of the mutation in the VHL protein leads to phenotypic manifestations in the pattern of cancer that develops.

First, they are more sensitive to the effects of growth factors created downstream of HIF activation than other cells.

Over time, sporadic mutation in the second copy of the VHL protein can lead to carcinomas, in particular hemangioblastomas affecting the liver and kidneys, renal (and vaginal) clear cell adenocarcinomas.

Inhibitors of VEGF receptor sorafenib, sunitinib, pazopanib, and recently axitinib have been approved by the FDA.

[10] The mTOR inhibitor rapamycin[20] analogs everolimus and temsirolimus or VEGF monoclonal antibody bevacizumab may also be an option.

The regulation of HIF1α by pVHL. Under normal oxygen levels, HIF1α binds pVHL through 2 hydroxylated proline residues and is polyubiquitinated by pVHL. This leads to its degradation via the proteasome. During hypoxia, the proline residues are not hydroxylated and pVHL cannot bind. HIF1α causes the transcription of genes that contain the hypoxia response element. In VHL disease, genetic mutations cause alterations to the pVHL protein, usually to the HIF1α binding site.