The von Hippel–Lindau () gene is a two-hit tumor suppressor gene and is linked to the development of the most common form of kidney cancer, clear cell renal carcinoma; blood vessel tumors of the retina, cerebellum, and spinal cord called hemangioblastomas; and tumors of the sympathoadrenal nervous system called paragangliomas. The gene product, pVHL, is the substrate recognition subunit of a cullin-dependent ubiquitin ligase that targets the α subunits of hypoxia-inducible factor (HIF) for destruction when oxygen is plentiful. Mounting evidence implicates HIF2 in the pathogenesis of pVHL-defective tumors and has provided a conceptual foundation for the development of drugs to treat them that inhibit HIF2-responsive gene products such as VEGF and, more recently, HIF2 itself. pVHL has additional, noncanonical functions that are cancer relevant, including roles related to the primary cilium, chromosome stability, extracellular matrix formation, and survival signaling.


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