Small Maf Proteins Heterodimerize with Fos and May Act as Competitive Repressors of the NF-E2 Transcription Factor

Abstract

The maf oncogene encodes a bZip nuclear protein which recognizes sequences related to an AP-1 site either as a homodimer or as heterodimers with Fos and Jun. We describe here a novel maf-related gene, mafG, which shows extensive homology with two other maf-related genes, mafK and mafF. These three maf-related genes encode small basic-leucine zipper proteins lacking the trans-activator domain of v-Maf. Bacterially expressed small Maf proteins bind to DNA as homodimers with a sequence recognition profile that is virtually identical to that of v-Maf. As we have previously described, the three small Maf proteins also dimerize with the large subunit of NF-E2 (p45) to form an erythroid cell-specific transcription factor, NF-E2, which has distinct DNA-binding specificity. This study shows that the small Maf proteins can also dimerize among themselves and with Fos and a newly identified p45-related molecule (Ech) but not with v-Maf or Jun. Although the small Maf proteins preferentially recognize the consensus NF-E2 sequence as heterodimers with either NF-E2 p45, Ech, or Fos, these heterodimers seemed to be different in their transactivation potentials. Coexpression of Fos and small Mafs could not activate a promoter with tandem repeats of the NF-E2 site. These results raise the possibility that tissue-specific gene expression and differentiation of erythroid cells are regulated by competition among Fos, NF-E2 p45, and Ech for small Maf proteins and for binding sites.The maf oncogene was identified by structural analysis of the genome of the AS42 avian transforming retrovirus (26,40). It encodes a nuclear basic-leucine zipper (bZip) protein which can form a homodimer through its zipper structure (23). Recently, we reported that the v-Maf homodimer specifically recognizes two relatively long palindromic DNA sequences, TGCTGACTCAGCA and TGCTGACGTCAGCA, at roughly equal efficiency (24). The middle parts of the two consensus binding sequences for Maf are identical with two well-characterized binding sequences of the AP-1 transcription factor, the 12-O-tetradecanoylphorbol-13-acetate (TPA)-responsive element (TRE; TGACTCA) and the cyclic AMP-responsive element (CRE; TGACGTCA), respectively. We therefore named the two types of recognition elements TRE-type Maf recognition elements (MAREs) and CRE-type MAREs. It was also recently revealed that Maf forms heterodimers with the two major components of AP-1, Fos and Jun (24, 27, 28). These heterodimers preferably bind to asymmetric DNA sequences consisting of the two consensus binding sequences of Maf homodimer and AP-1 (24). Thus, Maf and the two AP-1 components are suggested to interact with each other in a cooperative or inhibitory way in association with their recognition sequences by forming heterodimers of altered binding specificities.Like many other proto-oncogenes, the c-maf gene is a member of a gene family. To date, four maf-related genes, mafK, mafF, mafB, and nrl, have been reported (14,22,53). Their gene products are closely related to v-Maf especially in the structur...

c-Jun inhibits NF-E2 transcriptional activity in association with p18/maf in Friend erythroleukemia cells

“…Since it was reported that Maf/Jun heterodimers can bind NF-E2/ AP-1 like sites more e ciently than c-Jun homodimers or Maf homodimers Kerppola and Curran, 1994), NF-E2 activity may be repressed by formation of c-Jun/NF-E2p18 heterodimers that are unable to activate transcription from these sites. Similarly, recent studies have shown that c-Fos can act as a negative regulator of transcription in combination with the small Maf proteins (Kataoka et al, 1995). Although we favor the model of inactive cJun/p18 complexes, two alternative explanations of our results may be considered.…”

“…Homodimers of small Maf proteins suppress transcription from NF-E2/AP-1 sites in non-erythroid cells (Igarashi et al, 1994). Maf proteins could also heterodimerize with bZip proteins from the Fos/Jun family (Kataoka et al, , 1995Kerpola and Curran, 1994). The Jun/Maf heterodimers have binding speci®cities distinct from those of the Jun/Jun and Maf/Maf homodimers but their transcriptional activity has not yet been reported.…”

Human small Maf proteins form heterodimers with CNC family transcription factors and recognize the NF-E2 motif

“…As is the case for chicken small Maf proteins (Fujiwara et al, 1993;Kataoka et al, 1995) and mouse MafK (Andrews et al, 1993b;Igarashi et al, 1995a), human MafK and MafG contain a basic domain and a leucine zipper domain, but lack any canonical transactivation domains. The human MafK sequence was established to show 96% and 95% identity with its chicken and mouse counterparts, respectively, while the human MafG sequence showed 94% identity with that of chicken MafG (Figure 3).…”

Mouse MafA, homologue of zebrafish somite Maf 1, contributes to the specific transcriptional activity through the insulin promoter

“…The large Maf proteins, MafA/L-Maf/ SMaf1 [3][4][5], MafB [6], c-Maf [7], and Nrl [8], contain an acidic domain in their N-termini that acts as a transcriptional activation site. By contrast, the small Maf proteins, MafK, MafF [9], and MafG [10], lack such an acidic domain.…”