VHLmediated

VHLmediated refers to cellular processes governed by the von Hippel-Lindau (VHL) tumor suppressor protein, particularly its role as the substrate-recognition component of a Cullin-2-based E3 ubiquitin ligase that targets hypoxia-inducible factor alpha (HIF-α) for proteasomal degradation under normoxic conditions. In oxygenated conditions, prolyl hydroxylases modify HIF-α, enabling pVHL to bind HIF-α and recruit the Elongin B/C, Cullin-2, and Rbx1 core to polyubiquitinate HIF-α, marking it for degradation and preventing hypoxia-responsive gene activation.

Under hypoxic conditions, reduced prolyl hydroxylation stabilizes HIF-α, allowing it to accumulate, dimerize with HIF-β, and translocate to the nucleus to activate transcription of genes involved in angiogenesis, erythropoiesis, and metabolism. Key target genes include vascular endothelial growth factor (VEGF), erythropoietin (EPO), and glycolytic enzymes, enabling cellular adaptation to low oxygen.

The VHL-containing E3 ligase complex (CRL2-VHL) comprises pVHL, Elongin B/C, Cullin-2, and Rbx1, with regulatory inputs from post-translational modifications and cellular oxygen levels. While HIF-α is the principal substrate in the context of oxygen sensing, the VHL pathway influences additional cellular processes reported in the literature, though these are less consistently characterized.

Clinical relevance centers on von Hippel-Lindau disease, caused by germline VHL mutations, which predispose to retinal and CNS hemangioblastomas, clear cell renal cell carcinoma, and pheochromocytoma. Somatic VHL loss is common in sporadic ccRCC, resulting in constitutive HIF signaling and tumor progression. The VHL–HIF axis is a therapeutic target, with HIF-2α inhibitors and anti-angiogenic strategies employed to treat VHL-related tumors and certain cancers.