Tumor angiogenesis is driven primarily by hypoxia-induced transcription factor HIF-1α upregulating VEGF. Which enzyme degrades HIF-1α under normoxic conditions, targeting it for proteasomal destruction via the VHL E3 ubiquitin ligase complex?

• A Factor inhibiting HIF-1 (FIH) asparaginyl hydroxylase
• B RACK1 ubiquitin ligase acting independently of oxygen
• C GSK-3β kinase phosphorylating HIF-1α at serine 551
• D Prolyl hydroxylase domain (PHD) enzymes ✓

Explanation

Under normoxic conditions, prolyl hydroxylase domain (PHD) enzymes hydroxylate specific proline residues (Pro402 and Pro564) on HIF-1α using molecular oxygen as co-substrate. Hydroxylated HIF-1α is then recognised by the VHL protein, part of an E3 ubiquitin ligase complex, leading to polyubiquitination and proteasomal degradation. In hypoxia or when VHL is mutated (as in clear cell renal cell carcinoma), PHD activity is impaired, HIF-1α accumulates, and VEGF-driven angiogenesis is constitutively activated.

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

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