FUNCTIONAL AND PHYSICAL ASSOCIATIONS BETWEEN NF-KAPPA-B AND C/EBP FAMILY MEMBERS - A REL DOMAIN-BZIP INTERACTION

NF-KB and C/EBP represent distinct families of transcription factors that target unique DNA enhancer elements. The heterodimeric NF-kappaB complex is composed of two subunits, a 50- and a 65-kDa protein. All members of the NF-kappaB family, including the product of the proto-oncogene c-rel, are characterized by their highly homologous approximately 300-amino-acid N-terminal region. This Rel homology domain mediates DNA binding, dimerization, and nuclear targeting of these proteins. C/EBP contains the bZIP region, which is characterized by two motifs in the C-terminal half of the protein: a basic region involved in DNA binding and a leucine zipper motif involved in dimerization. The C/EBP family consists of several related proteins, C/EBPalpha, C/EBPbeta, C/EBP-gamma, and C/EBPdelta, that form homodimers and that form heterodimers with each other. We now demonstrate the unexpected cross-coupling of members of the NF-kappaB family with three members of the C/EBP family. NF-kappaB p65, p50, and Rel functionally synergize with C/EBPalpha, C/EBPbeta, and C/EBPdelta. This cross-coupling results in the inhibition of promoters with kappaB enhancer motifs and in the synergistic stimulation of promoters with C/EBP binding sites. These studies demonstrate that NF-kappaB augments gene expression mediated by a multimerized c-fos serum response element in the presence of C/EBP. We show a direct physical association of the bZIP region of C/EBP with the Rel homology domain of NF-kappaB. The cross-coupling of NF-kappaB with C/EBP highlights a mechanism of gene regulation involving an interaction between distinct transcription factor families.