The hypoxia-inducible factor 2α N-terminal and C-terminal transactivation domains cooperate to promote renal tumorigenesis in vivo

Hypoxia-inducible factor (HIF) is a heterodimeric transcription factor, consisting of an alpha subunit and a beta subunit, that controls cellular responses to hypoxia. HIF alpha contains two transcriptional activation domains called the N-terminal transactivation domain (NTAD) and the C-terminal transactivation domain (CTAD). HIF alpha is destabilized by prolyl hydroxylation catalyzed by EgIN family members. In addition, CTAD function is inhibited by asparagine hydroxylation catalyzed by FIH1. Both hydroxylation reactions are linked to oxygen availability. The von Hippel-Lindau tumor suppressor protein (pVHL) is frequently mutated in kidney cancer and is part of the ubiquitin ligase complex that targets prolyl hydroxylated HIF alpha for destruction. Recent studies suggest that HIF2 alpha plays an especially important role in promoting tumor formation by pVHL-defective renal carcinoma cells among the three HIF alpha paralogs. Here we dissected the relative contribution of the two HIF2 alpha transactivation domains to hypoxic gene activation and renal carcinogenesis and investigated the regulation of the HIF2a CTAD by FIHI. We found that the HIF2a NTAD is capable of activating both artificial and naturally occurring HIF-responsive promoters in the absence of the CTAD. Moreover, we found that the HIF2 alpha CTAD, in contrast to the HIF1 alpha CTAD, is relatively resistant to the inhibitory effects of FIHI under normoxic conditions and that, perhaps as a result, both the NTAD and CTAD cooperate to promote renal carcinogenesis in vivo.