Figure 7.
Effect of HAF on tumor growth in vivo. A, survival curve when 500,000 vector or HAF U87 cells (adherent population only) were injected intracranially. B and C, survival curve of mice injected intracranially with 100,000 or 5,000 pooled floating and adherent cell populations (*, P = 0.00425). D, diagram showing mechanism of the HAF-induced switch from HIF-1α to HIF-2α signaling. The C-terminal E3 ubiquitin ligase domain of HAF binds to HIF-1α close to its oxygen-dependent degradation domain (ODD) and ubiquitinates it, targeting it for proteasomal degradation, whereas the central domain of HAF binds close to the C-TAD of HIF-2α, hence promoting HIF-2α transactivation. E, diagram showing the proposed role of HAF in regulating the kinetics of the HIF-1/2α activation in response to continuous hypoxia. During the early/acute hypoxic response, HAF protein levels decrease which facilitates the activation of HIF-1α but limits HIF-2α–dependent transcription. During prolonged/chronic hypoxia, HAF levels gradually increase in which it cooperates with HIF-2α to promote transcription.