loss of function is associated with the Von Hippel-Lindau disease
Product of the VHL gene is the protein pVHL.
Function of pVHL is ubiquitylation of HIF-1α, which is one of two subunits of the HIF-1(hypoxia-inducible factor-1) transcription factor.
Polyubiquitylation of HIF-1α leads to its degradation and therefore prevents the formation of a functional HIF-1.
A functional HIF-1 transcription factor causes expression of genes such as VEGF, PDGF, TGF-α, which are growth promoting genes in the context of establishing new blood vessels.
Normally, pVHL constitutively prevents HIF-1 to become active, but if the cell experiences hypoxia, pVHL fails to bind to the HIF-1α subunit and therefore an adequate stimulation of angiogenesis and erythropoiesis will establish an sufficient oxygen supply for the cells suffering hypoxia.
If pVHL cannot form, since VHL was deactivatied by (e.g.) mutation, HIF-1α is constitutively active, which leads to an inappropriate high level of these growth factors, which will favor tumor growth.
Loss of function can contribute to the development of Familial adenomatous polyposis (FAP)
Together with GSK-3β and axin Apc builds the β-catenin destruction complex, which playes a key role in the wnt-signalling pathway.
In colonic crypts, Apc negatively controls the levels of β-catenin, which governs the proliveration of the enterocytes in the crypt:
Cells are produced at the bottom of the crypt and migrate upward to the villus.
β-catenin levels decrease coninously from the lower crypt to the upper villus. This is because the migrating cells increase the expression of APC which, in the absence of Wnts, is able to break down β-catenin.
The absence of β-catenin drives cells to differentiation.
If APC is mutated and therefore not able to build the β-catenin destruction complex, β-catenin levels stay high and prevent cells from differentiation.
Continuous proliferation and the formation of polyps is the consequence.