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

Cells exposed to hypoxia undergo substantial changes in gene expressio n generally associated with metabolic adaptation and increasing oxygen delivery. In contrast, responses distinct from those elicited by hypo xia are induced in anoxic fibroblasts; this includes activation of a s et of VL30 elements. The responses seen in anoxically cultured fibrobl asts are expressed physiologically in vivo during the anaerobic phase of mound healing. A fundamental question is whether transcriptional re gulatory pathways utilized during anoxia are distinct from those alrea dy characterized for hypoxic cells. We report here the isolation of a 14-bp sequence within a VL30 retrotransposon promoter which mediates i ts 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 f ibroblasts and is indistinguishable from hypoxia-inducible factor 1. T he second activity, which is present only in anoxic fibroblasts, is a previously uncharacterized heterodimeric DNA binding activity that app ears to arise via posttranslational modification of an existing comple x found in aerobic cells. These results indicate that the strong VL30 transcriptional induction seen with anoxia occurs through a mechanism specific to anoxia.