von Hippel-Lindau tumor suppressor protein (pVHL)

The von Hippel-Lindau tumor suppressor protein (pVHL) is a 213-amino-acid cytoplasmic protein that functions primarily as a substrate recognition subunit in an E3 ubiquitin ligase complex, targeting hypoxia-inducible factor (HIF) alpha subunits—especially HIF1α and HIF2α—for proteasomal degradation under normoxic conditions, thereby suppressing hypoxia-responsive genes like VEGF that drive angiogenesis and cell proliferation. Loss-of-function mutations in the VHL gene, the most common genetic alteration in clear cell renal cell carcinoma, lead to HIF stabilization, uncontrolled tumor growth, and vascularization, forming the basis of von Hippel-Lindau hereditary cancer syndrome characterized by tumors in the kidney, brain, spine, eyes, adrenal glands, pancreas, and inner ear. Beyond canonical HIF regulation, pVHL supports noncanonical roles including extracellular fibronectin matrix assembly, primary cilium integrity, chromosome stability, and neuronal differentiation in cells like neuroblastoma, where its overexpression induces neurite outgrowth, neurofilament expression, and voltage-gated ion channel activity while downregulating proliferation-associated EAG potassium channels. Therapeutically, pVHL loss has spurred development of HIF2 inhibitors like belzutifan, approved for VHL-associated renal cell carcinoma, which mimic pVHL's degradative function by directly blocking HIF2 dimerization and transcriptional activity. Challenges include balancing HIF inhibition against broader effects on cell survival signaling and tissue homeostasis.

Other names

VHL proteinVHL tumor suppressorpVHL19pVHL30

Inhibition of HIF2-responsive genes (e.g., VEGF), Direct HIF2 inhibition, Promotion of HIF-alpha ubiquitination and degradation