Fig. 9. Regulation of mammalian glycolytic enzyme genes by the HIF-1 and Sp1 family transcription factors. A proline residue at position 564 on the HIF-1 protein (illustrated as a helix-turn-helix structure) is hydroxylated at physiological oxygen tension, causing a conformational change and rendering the protein susceptible to ubiquitination (Ub). Ubiquitinated protein is rapidly degraded by the proteosome. Under hypoxia, this pathway is blocked; HIF-1 accumulates, dimerizes the aryl hydrocarbon nuclear transporter (ARNT), translocates to the nucleus, and activates responsive genes including glycolytic enzymes by binding to sequences containing the consensus ACGT site. In a second redox-regulated step, p300 can only be recruited to activate the HIF-1 complex when the Asp-851 residue is not hydroxylated. In a parallel hypoxia-regulated pathway, Sp1 and Sp3 (zinc fingers) compete for binding to GC-rich DNA sequences; Sp1 is a positive transcriptional activator while Sp3 can repress transcription. Hypoxia favors degradation of Sp3 (by an unknown mechanism), promoting the full inducing activity of Sp1.