In sporadic clear cell renal cell carcinoma arising in patients with von Hippel-Lindau disease, loss of the VHL protein produces tumour angiogenesis because pVHL normally:

• A Phosphorylates VEGF receptors on endothelial cells
• B Inhibits mTOR signalling downstream of PI3K
• C Binds beta-catenin and targets it for proteasomal destruction
• D Acts as the substrate-recognition component of an E3 ubiquitin ligase that degrades HIF-1alpha under normoxic conditions ✓

Explanation

pVHL recognises hydroxylated HIF-1alpha and directs its polyubiquitination for proteasomal degradation when oxygen is available. With VHL loss, HIF-1alpha accumulates even at normal oxygen tension and drives transcription of VEGF, GLUT1 and EPO, explaining the hypervascularity, possible paraneoplastic polycythemia and haemangioblastomas of the syndrome. Beta-catenin is the target of APC, and mTOR inhibition is a therapeutic effect of drugs such as everolimus, not a pVHL function.

Reference: Robbins and Cotran Pathologic Basis of Disease, 10th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.