FIGURE 10.
Model of the role of TACC3 within HIF-2 transcriptional activation. HIF complexes are bHLH-PAS heterodimers that include an O2-sensitive HIF-α subunit and a constitutive ARNT subunit. Under normoxia, O2-dependent hydroxylation of HIF-2α decreases its abundance and activity (red arrows) (2). Such modifications do not happen on ARNT and TACC3 so the ARNT·TACC3 complex is readily assembled in the nucleus. Hypoxia stops the hydroxylation, allowing HIF-2α to accumulate in the nucleus and complex with ARNT·TACC3. Here, we propose that TACC3 simultaneously engages the PAS-B domains from both HIF-2α and ARNT PAS-B, directing recruitment of this CCC protein to hypoxia-responsive enhancer (HRE) sites, controlling target gene transcription (blue arrows).