The role of ARNT2 in tumor angiogenesis and the neural response to hypoxia

The Hypoxia-Inducible Factor-1 (HIF-1) activates the transcription of many genes required for cellular and organismal responses to oxygen deprivation. The HIF-1 complex is composed of the ubiquitously expressed basic helix-lo op-helix/PAS (bHLH/PAS) proteins HIF-1 alpha and Arylhydrocarbon Receptor N uclear Translocator (ARNT). ARNT2 is a conserved ARNT homolog that is highl y expressed in neurons, suggesting that ARNT2/HIF-1 alpha heterodimers medi ate transcriptional responses to oxygen deprivation in the nervous system. We show here that ARNT2 forms functional HIF complexes in vivo, and that AR NT2 restores hypoxia-induced gene expression to ARNT-deficient ES cells and hepatocytes. Formation of neural ARNT2/HIF-1 alpha complexes in Arnt(-/-) ES cell-derived teratocarcinomas may explain why these tumors express VEGF, vascularize and grow efficiently, in contrast to ARNT-deficient hepatomas. Interestingly, all neural cell types studied accumulate both ARNT- and ARN T2-containing HIF complexes. We conclude that ARNT2 forms functional HIF co mplexes in neurons and plays an integral role in hypoxic responses in the C NS. (C) 2000 Academic Press.