Which of the following best describes the molecular mechanism by which loss of VHL tumor suppressor gene function leads to clear cell renal cell carcinoma?

• A Increased ubiquitination and proteasomal degradation of HIF-1α
• B Failure to ubiquitinate HIF-1α, causing constitutive upregulation of VEGF and PDGF ✓
• C Activation of mTORC1, leading to increased protein synthesis
• D Inactivation of the Wnt/β-catenin pathway

Explanation

The VHL protein forms a ubiquitin ligase complex that normally targets HIF-1α for proteasomal degradation under normoxic conditions. Loss-of-function VHL mutations prevent this degradation, leading to constitutive HIF-1α activity which transcriptionally upregulates VEGF, PDGF-B, EPO, and glucose transporters — driving angiogenesis, growth, and the characteristic clear cell (glycogen/lipid-rich) morphology. This is also the mechanism in von Hippel-Lindau hereditary syndrome.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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