- The von Hippel–Lindau protein (pVHL) is a tumor suppressor protein encoded by the VHL gene located on chromosome 3p25–26.
- It is best known for its role in oxygen sensing and regulation of hypoxia-inducible factors (HIFs), making it a central player in cellular adaptation to oxygen availability.
- Structurally, pVHL forms part of an E3 ubiquitin ligase complex, commonly referred to as the VBC complex, composed of pVHL, elongin B, elongin C, cullin-2, and Rbx1. Through this complex, pVHL regulates the ubiquitination and subsequent proteasomal degradation of HIF-α subunits under normal oxygen conditions. This function establishes pVHL as the molecular “gatekeeper” of the hypoxia response pathway.
- Under normoxic conditions, specific proline residues on HIF-α are hydroxylated by oxygen-dependent prolyl hydroxylase domain (PHD) enzymes. Hydroxylation creates a recognition site for pVHL, which binds to HIF-α and recruits the ubiquitin-proteasome machinery, leading to HIF-α degradation. When oxygen levels drop, hydroxylation is inhibited, preventing pVHL from binding HIF-α. As a result, HIF-α stabilizes, translocates into the nucleus, and dimerizes with HIF-β to activate hypoxia-response elements (HREs) in target genes. This regulatory switch controlled by pVHL is essential for balancing angiogenesis, erythropoiesis, metabolism, and cell survival during hypoxic stress.
- Beyond its canonical role in oxygen sensing, pVHL is involved in other cellular processes, including regulation of microtubule stability, extracellular matrix assembly, and maintenance of primary cilia. pVHL has been shown to interact with fibronectin, collagen IV, and integrins, highlighting its role in maintaining proper cell adhesion and tissue architecture. Disruption of these functions, alongside loss of HIF regulation, contributes to the pathological consequences of VHL mutations.
- Mutations in the VHL gene give rise to von Hippel–Lindau disease, a hereditary cancer syndrome characterized by predisposition to a range of highly vascularized tumors, including hemangioblastomas of the central nervous system and retina, renal cell carcinomas, pheochromocytomas, and pancreatic neuroendocrine tumors. Loss of functional pVHL leads to constitutive HIF activation, resulting in uncontrolled expression of pro-angiogenic and pro-survival genes such as vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF). This “pseudo-hypoxic” state fuels tumorigenesis by promoting angiogenesis and metabolic reprogramming.
- Clinically, the discovery of pVHL’s role in the hypoxia pathway has had significant therapeutic implications. Targeting downstream effectors of aberrant HIF activation, such as VEGF, has led to the development of anti-angiogenic therapies like bevacizumab and tyrosine kinase inhibitors used in renal cell carcinoma treatment. More recently, direct inhibitors of HIF-2α have shown promise in clinical trials for VHL-associated tumors. Furthermore, the elucidation of the pVHL–HIF–oxygen-sensing mechanism was recognized by the awarding of the 2019 Nobel Prize in Physiology or Medicine to William Kaelin, Peter Ratcliffe, and Gregg Semenza.
