Erythropoietin (EPO) production in response to hypoxia is mediated by which transcription factor that is stabilised under low O2 conditions?

• A HIF-1α (hypoxia-inducible factor 1-alpha), which is normally hydroxylated by PHD enzymes and targeted for VHL-mediated ubiquitin-proteasomal degradation in normoxia ✓
• B HIF-2α is the exclusive mediator of EPO transcription in the kidney, while HIF-1α is not involved in erythropoiesis
• C GATA-1 transcription factor, which accumulates under hypoxia and binds GATA sites in the EPO promoter
• D NF-κB, which is activated by reactive oxygen species generated during hypoxia to induce EPO

Explanation

HIF-1α (and HIF-2α in the kidney) are the master regulators of the hypoxic response, including EPO gene expression. Under normoxia, prolyl hydroxylase domain enzymes (PHDs) use O2 as a cofactor to hydroxylate HIF-1α on proline residues; this enables recognition by the VHL E3 ubiquitin ligase complex, which ubiquitinates HIF-1α for proteasomal degradation. Under hypoxia, PHD activity falls, HIF-1α accumulates in the cytoplasm, translocates to the nucleus, heterodimerises with HIF-1β (ARNT), and binds hypoxia-response elements (HRE) to transactivate target genes including EPO, VEGF, and GLUT-1. In the kidney, HIF-2α (EPAS1) is the principal isoform mediating renal EPO induction. HIF-2α inhibitors (vadadustat, daprodustat) are now used clinically for renal anaemia.

Reference: Guyton & Hall, Textbook of Medical Physiology, 14th ed.

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