The hypoxia-inducible factor 2alpha 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. HIFalpha contains two transcriptional activation domains called the N-terminal transactivation domain (NTAD) and the C-terminal transactivation domain (CTAD). HIFalpha is destabilized by prolyl hydroxylation catalyzed by EglN 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 HIFalpha for destruction. Recent studies suggest that HIF2alpha plays an especially important role in promoting tumor formation by pVHL-defective renal carcinoma cells among the three HIFalpha paralogs. Here we dissected the relative contribution of the two HIF2alpha transactivation domains to hypoxic gene activation and renal carcinogenesis and investigated the regulation of the HIF2alpha CTAD by FIH1. We found that the HIF2alpha NTAD is capable of activating both artificial and naturally occurring HIF-responsive promoters in the absence of the CTAD. Moreover, we found that the HIF2alpha CTAD, in contrast to the HIF1alpha CTAD, is relatively resistant to the inhibitory effects of FIH1 under normoxic conditions and that, perhaps as a result, both the NTAD and CTAD cooperate to promote renal carcinogenesis in vivo.
Yan
Qin
Q
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Bartz
Steven
S
Mao
Mao
M
Li
Lianjie
L
Kaelin
William G
WG
D000595:Amino Acid Sequence; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D017124:Conserved Sequence; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D051381:Rats; D016415:Sequence Alignment; D015533:Transcriptional Activation / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D000099162:Endothelial PAS Domain-Containing Protein 1