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 t hat target unique DNA enhancer elements. The heterodimeric NF-kappaB c omplex is composed of two subunits, a 50- and a 65-kDa protein. All me mbers of the NF-kappaB family, including the product of the proto-onco gene c-rel, are characterized by their highly homologous approximately 300-amino-acid N-terminal region. This Rel homology domain mediates D NA binding, dimerization, and nuclear targeting of these proteins. C/E BP contains the bZIP region, which is characterized by two motifs in t he C-terminal half of the protein: a basic region involved in DNA bind ing and a leucine zipper motif involved in dimerization. The C/EBP fam ily consists of several related proteins, C/EBPalpha, C/EBPbeta, C/EBP -gamma, and C/EBPdelta, that form homodimers and that form heterodimer s with each other. We now demonstrate the unexpected cross-coupling of members of the NF-kappaB family with three members of the C/EBP famil y. NF-kappaB p65, p50, and Rel functionally synergize with C/EBPalpha, C/EBPbeta, and C/EBPdelta. This cross-coupling results in the inhibit ion of promoters with kappaB enhancer motifs and in the synergistic st imulation of promoters with C/EBP binding sites. These studies demonst rate that NF-kappaB augments gene expression mediated by a multimerize d c-fos serum response element in the presence of C/EBP. We show a dir ect physical association of the bZIP region of C/EBP with the Rel homo logy domain of NF-kappaB. The cross-coupling of NF-kappaB with C/EBP h ighlights a mechanism of gene regulation involving an interaction betw een distinct transcription factor families.