ANOXIC INDUCTION OF A SARCOMA VIRUS-RELATED VL30 RETROTRANSPOSON IS MEDIATED BY A CIS-ACTING ELEMENT WHICH BINDS HYPOXIA-INDUCIBLE FACTOR-1 AND AN ANOXIA-INDUCIBLE FACTOR

Cells exposed to hypoxia undergo substantial changes in gene expression generally associated with metabolic adaptation and increasing oxygen delivery. In contrast, responses distinct from those elicited by hypoxia are induced in anoxic fibroblasts; this includes activation of a set of VL30 elements. The responses seen in anoxically cultured fibroblasts are expressed physiologically in vivo during the anaerobic phase of mound healing. A fundamental question is whether transcriptional regulatory pathways utilized during anoxia are distinct from those already characterized for hypoxic cells. We report here the isolation of a 14-bp sequence within a VL30 retrotransposon promoter which mediates its anoxia responsiveness. Analyses of the protein complexes binding to this sequence demonstrated the presence of two distinct inducible DNA binding activities. The first is present in both hypoxic and anoxic fibroblasts and is indistinguishable from hypoxia-inducible factor 1. The second activity, which is present only in anoxic fibroblasts, is a previously uncharacterized heterodimeric DNA binding activity that appears to arise via posttranslational modification of an existing complex found in aerobic cells. These results indicate that the strong VL30 transcriptional induction seen with anoxia occurs through a mechanism specific to anoxia.