A 1.6-kilobase pair full-length cDNA encoding a transcription factor homologous to the Maf family of proteins was isolated by screening a K562 cDNA library with the NFE2 tandem repeat probe derived from the globin locus control region. The protein, which was designated hMAF, contains a basic DNA binding domain and an extended leucine zipper but lacks any recognizable activation domain. Expressed in vitro, the hMAF protein is able to homodimerize in solution and bandshift the NFE2 tandem repeat probe. In addition to homodimers, hMAF can also form high affinity heterodimers with two members of the NFE2/CNC-bZip family (Nrf1 and Nrf2) but not with a third family member, p45-NFE2. Although hMAF/hMAF homodimers and hMAF/Nrf1 and hMAF/Nrf2 heterodimers bind to the same NFE2 site, they exert functionally opposite effects on the activity of a linked ␥-globin gene. In fact, whereas all hMAF/CNC-bZip heterodimers stimulate the activity of a ␥-promoter reporter construct in K562 cells, the association into homodimers that is induced by overexpressing hMAF inhibits the activity of the same construct. Thus variations in the expression of hMAF may account for the modulation in the activity of the genes that bear NFE2 recognition sites.In the last decade, meticulous searches along the -globin gene cluster have led to the identification of numerous regulatory DNA sequences located either in close proximity to the genes or at a distance in regions that were originally identified for their DNase I hypersensitivity (1-3). The latter regions, which are referred to individually as hypersensitive sites (from 5Ј-HS1 to HS4) and collectively as the locus control region of the -globin gene cluster (4), contain elements with different functions such as enhancers (5-8), silencers (9, 10), origins of replication (11-13), and putative insulators (14). By a series of structural and functional experiments based on DNA-protein interactions (15-23) as well as selective mutagenesis and expression studies in cell lines and transgenic mice (17,18,(22)(23)(24)(25)(26)(27), several short DNA consensus sequences have been identified to bind regulatory proteins that represent the effectors of the activities ascribed to the locus control region. One such sequence (TGAGTCA) that is repeated twice in the core of the HS2 enhancer is recognized by proteins of the AP1 (28), cAMPresponsive element-binding protein, and NFE2/CNC-bZip families of transcription factors (29,30) and is known as the NFE2/ AP1 consensus sequence. As the latter motif is frequently found along the globin clusters in DNA elements with enhancer activity, cloning p45-NFE2 (31-33) has raised much interest as it could provide useful insights on the transcription factor enhancement of the globin gene expression, which in turn might lead to novel therapeutic approaches for inherited hemoglobin diseases such as sickle cell and thalassemia syndromes.Soon after the cloning of NFE2, we and others have cloned two more genes, NRF1 (also known as LCR-F1 and TCF11) (34 -36) and NRF2 (37), which is...