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Figure 2

Regulation of HIF-1α in response to mutations in metabolic enzymes. (A) HIF-1α is hydroxylated at proline residues by the PHD enzymes, a reaction that requires α-ketoglutarate and produces succinate. Hydroxylated HIF-1α is ubiquitinated by a VHL-containing ubiquitin ligase. (B) Mutations in SDH or FH enzymes trigger accumulation of succinate, impairing HIF-1α hydroxylations. Increased HIF-1α drives increased glycolysis. (C) Mutant forms of IDH1 or IDH2 (marked with an asterisk) may reduce the availability of α-ketoglutarate, restricting HIF-1α hydroxylation and activating glycolysis. An alternative model proposes that mutated IDH enzymes acquire a novel activity, producing increased 2-hydroxyglutarate. The effects of 2-hydroxyglutarate on the signal transduction and metabolism of transformed cells are not yet well described.

This Article

  1. Endocr Relat Cancer vol. 17 no. 4 R287-R304