Fig. 9.

Schematic representation of the roles of long HIF-3α variants in the hypoxia response. a When HIF-β is not limiting, HIF-1α, HIF-2α, and the long HIF-3α variants mainly associate with HIF-β and activate hypoxia-inducible target genes. Our data suggest that the long HIF-3α variants are required for maximal activation of certain HIF target genes and are likely to have target elements distinct from the canonical HRE response element. b When the amount of HIF-β is limiting, the long HIF-3α variants associate with HIF-1α and HIF-2α leading to decreased activation of HIF target genes. The short variant HIF-3α4, which is not depicted in the scheme, forms inactive complexes with HIF-1α, HIF-2α and HIF-β and causes downregulation of HIF target genes independent on whether HIF-β is non-limiting or limiting. Formation of these complexes is also dependent on the relative amounts of HIF-3α4, HIF-1α, HIF-2α and HIF-β