A child with von Hippel-Lindau (VHL) disease develops cerebellar haemangioblastoma. The VHL protein normally ubiquitinates which transcription factor to target it for proteasomal degradation?

• A VEGF mRNA directly
• B HIF-1alpha (hypoxia-inducible factor) ✓
• C c-Myc oncoprotein
• D p53 tumour suppressor

Explanation

pVHL is the substrate recognition subunit of an E3 ubiquitin ligase complex that, in normoxia, recognises hydroxylated HIF-1alpha (hydroxylated by prolyl hydroxylases) and marks it for proteasomal degradation. Loss of pVHL (as in VHL disease) prevents HIF-1alpha degradation, causing constitutive transcription of HIF target genes including VEGF, PDGF, and EPO, driving haemangioblastoma, clear cell renal carcinoma, and polycythaemia. VHL does not directly ubiquitinate VEGF mRNA, c-Myc, or p53.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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