A tumor suppressor gene product normally promotes ubiquitin-mediated degradation of HIF-1alpha under normoxic conditions. Loss of this gene leads to constitutive HIF-1alpha activity, angiogenesis, and clear cell carcinoma. Which gene is this?
- A TP53
- B VHL ✓
- C PTEN
- D RB1
Correct answer: B. VHL
Explanation
The VHL protein is part of an E3 ubiquitin ligase complex that targets hydroxylated HIF-1alpha for proteasomal degradation under normoxic conditions. Loss of VHL in clear cell renal cell carcinoma leads to constitutive HIF-1alpha activity, driving VEGF and EPO transcription. This explains the highly vascular nature of clear cell RCC and why VHL-mutant tumors respond to anti-VEGF therapy.
Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
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