pVHL

pVHL, or von Hippel-Lindau tumor suppressor protein, is the protein product of the VHL gene in humans and a core component of a cullin-RING E3 ubiquitin ligase complex known as CRL2^VHL. It functions as the substrate recognition unit of this complex, guiding ubiquitination and proteasomal degradation of specific targets.

Two major protein isoforms arise from the VHL transcript: pVHL30 and pVHL19. The longer pVHL30 contains an N-terminal acidic domain, while pVHL19 lacks this region; both isoforms can assemble with CUL2 and the Elongin B/C complex to form the CRL2^VHL ligase and regulate substrate degradation.

The primary physiological role of pVHL is to regulate cellular responses to oxygen. In normoxia, prolyl hydroxylases (PHD1-3) hydroxylate hypoxia-inducible factor alpha (HIF-α) subunits, such as HIF-1α and HIF-2α. Hydroxylated HIF-α is recognized by pVHL, leading to ubiquitination and proteasomal degradation, thereby suppressing hypoxia-responsive gene expression. Under hypoxic conditions, stabilization of HIF-α allows it to accumulate, translocate to the nucleus, dimerize with HIF-β, and activate genes involved in angiogenesis, metabolism, and erythropoiesis (e.g., VEGF, PDGF, EPO).

Mutations or loss of VHL function contribute to tumorigenesis by constitutive HIF activation, most notably in clear cell renal cell carcinoma. Germline VHL mutations cause von Hippel-Lindau disease, a hereditary cancer predisposition characterized by retinal and CNS hemangioblastomas, clear cell RCC, pheochromocytoma, and other lesions. VHL disease shows several subtypes (Type 1 and Type 2, including 2A, 2B, 2C) reflecting differing risks of pheochromocytoma and RCC.

Beyond HIF regulation, pVHL has HIF-independent roles in maintaining microtubule stability, ciliogenesis, and extracellular matrix organization, reflecting additional layers of tumor-suppressive activity.