Identity of GABP with NRF-2, a Multisubunit Activator of Cytochrome Oxidase Expression, Reveals a Cellular Role for an ETS Domain Activator of Viral Promoters

The ETS domain proteins are a diverse family of transcriptional activators that have been implicated recently in the expression of a number of cell-specific and viral promoters. Nuclear respiratory factor 2 (NRF-2) is a nuclear transcription factor that activates the proximal promoter of the rat cytochrome c oxidase subunit IV (RCO4) gene through tandem sequence elements. These elements conform to the consensus for high-affinity ETS domain recognition sites. We have now purified NRF-2 to homogeneity from HeLa cells and find that it consists of five polypeptides, only one of which has intrinsic DNA-binding ability. The others participate in the formation of heteromeric complexes with distinct binding properties. NRF-2 also specifically recognizes multiple binding sites in the mouse cytochrome c oxidase subunit Vb (MCO5b) gene. As in the functionally related RCO4 gene, tandemly arranged NRF-2 sites are essential for the activity of the proximal MCO5b promoter, further substantiating a role for NRF-2 in respiratory chain expression. Determination of peptide sequences from the various subunits of HeLa NRF-2 reveals a high degree of sequence identity with mouse GA-binding protein (GABP), a multisubunit ETS domain activator of herpes simplex virus immediate early genes. A cellular role in the activation of nuclear genes specifying mitochondrial respiratory function is thus assigned to an ETS domain activator of viral promoters.