Oxygen-Dependent Gene Expression and the HIF in Mammals
In mammals, research over the past decade points to a central role of the hypoxia-inducible factor (HIF) in the regulation of gene expression during hypoxia. HIF was discovered in studies of the regulation of erythropoietin (EPO) expression in the mammalian Hep3B cell line (94). It is a heterodimeric transcription factor comprised of HIF- and HIF- subunits, both of which are members of the PAS-domain family of transcription factors (named for the first members of the family, Per, ARNT, Sim). Three forms of -subunit have been described, HIF-1, HIF-2 (123), and HIF-3 (26). The -subunit is the same as the previously described aryl hydrocarbon receptor nuclear translocator (ARNT). In addition to its role in hypoxic signaling, ARNT plays other roles in gene regulation. For example, it dimerizes with the aryl hydrocarbon receptor during xenobiotically induced gene expression, thus playing a role in the response of cells to dioxins and other hydrocarbon pollutants (27, 28). After the discovery of HIF and its role in the hypoxic induction of EPO, HIF was found to be expressed in a variety of cell types and to be involved in the hypoxic regulation of a variety of genes (5, 83, 92, 118, 119). Because of the widespread expression of HIF and the diverse roles of HIF targets, this transcription factor has been likened to a “master switch” of the molecular response to low oxygen in mammals (92, 118). The o
