Hypoxia-inducible factor-2α (HIF-2α) is involved in the apoptotic response to hypoglycemia but not to hypoxia

Deprivation of oxygen (hypoxia) and/or glucose (hypoglycemia) represents a serious stress that affects cellular survival. The hypoxia-inducible transcription factor-1 alpha (HIF-1 alpha), which has been implicated in the cellular response to hypoxia (Semenza, G. L. (1999) Annu. Rev. Cell Dev. Biol. 15, 551-578), mediates apoptosis during hypoxia (Halterman, M. W., Miller, C. C., and Federoff, H. J. (1999) J. Neurosci. 19,6818-6824 and Carmeliet, P., Dor, Y., Herbert, J. M., Fukumura, D., Brusselmans, K., Dewerchin, M., Neeman, M., Bono, F., Ahramovitch, R., Maxwell, P., Koch, C. J., Ratcliffe, P., Moons, L., Jain, R. K., Collen, D., and Keshet, E. (1998) Nature 394, 485-490), but the function of its homologue HIF-2 alpha remains unknown. Therefore, the role of HIF-2 alpha in cellular survival was studied by targeted inactivation of the HIF-2 alpha gene (HIF-2 alpha (-/-)) in murine embryonic stem (ES) cells. In contrast to HIF-1 alpha deficiency, loss of HIF-2 alpha did not protect ES cells against apoptosis during hypoxia. Both HIF-1 alpha (-/-) and HIF-2 alpha (-/-) ES cells were, however, resistant to apoptosis in response to hypoglycemia. When co-cultured with wild type ES cells, HIF-2 alpha (-/-) ES cells became rapidly and progressively enriched in hypoglycemia but not in hypoxia. Thus, HIF-1 alpha and HIF-2 alpha may have distinct roles in responses to environmental stress, and despite its name, HIF-2 alpha may be more important in the survival response to environmental variables other than the level of oxygen.