A 35-year-old man presents with a cerebellar hemangioblastoma and bilateral renal cell carcinoma. Genetic testing reveals a germline mutation in the VHL gene on chromosome 3p25. The VHL protein functions as part of an E3 ubiquitin ligase complex. Which substrate is primarily targeted for degradation by this complex?
- A p53
- B Beta-catenin
- C Hypoxia-inducible factor 1-alpha (HIF-1alpha) ✓
- D Cyclin D1
Correct answer: C. Hypoxia-inducible factor 1-alpha (HIF-1alpha)
Explanation
The VHL protein (pVHL) is the substrate recognition component of an E3 ubiquitin ligase complex that targets hypoxia-inducible factor 1-alpha (HIF-1alpha) for proteasomal degradation under normoxic conditions. Loss of VHL function leads to constitutive stabilization of HIF-1alpha, driving transcription of VEGF, erythropoietin, and other pro-angiogenic factors, explaining the highly vascular tumors (hemangioblastomas, clear cell RCC) seen in VHL syndrome. p53 is targeted by MDM2. Beta-catenin is targeted by the APC complex.
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.