Functional and physical associations between NF-kappa B and C/EBP family members: a Rel domain-bZIP interaction.

Abstract

NF-KB and C/EBP represent distinct families of transcription factors that target unique DNA enhancer elements. The heterodimeric NF-KB complex is composed of two subunits, a 50-and a 65-kDa protein. All members of the NF-cB family, including the product of the proto-oncogene c-rel, are characterized by their highly homologous -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/EBPa, C/EBP3, C/EBP-y, and C/EBP8, that form homodimers and that form heterodimers with each other. We now demonstrate the unexpected cross-coupling of members of the NF-cB family with three members of the C/EBP family. NF-cB p65, p50, and Rel functionally synergize with C/EBPa, C/EBPf3, and C/EBP8. This cross-coupling results in the inhibition of promoters with KB enhancer motifs and in the synergistic stimulation of promoters with C/EBP binding sites. These studies demonstrate that NF-KB 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-KB. The cross-coupling of NF-cB with C/EBP highlights a mechanism of gene regulation involving an interaction between distinct transcription factor families.Transcriptional regulation of gene expression is controlled by factors that bind to specific DNA sequences. Many of these factors can be classified into distinct families based on common structural motifs. These families include the homeodomain family (30), the zinc finger proteins (26, 46), the leucine zipper family (49,84), and the helix-loop-helix family (59, 60). Many of these transcription factors bind to their cognate DNA motifs as homodimers and, moreover, there are multiple examples of heterodimer formation within the same family of transcription factors. However, there is growing evidence that these dimerization motifs are also involved in interactions between transcription factors from different families. Examples are the interaction of the Jun leucine zipper region with the helix-loop-helix motif of MyoD (12) (24,42,74,87). This cross-coupling between different families might lead to the formation of novel transcription factor complexes displaying altered biological activities.The transcription factor NF-KB binds to KB enhancer motifs found in a variety of genes in response to various signals (5 and references therein, 35, 51). NF-KB DNA binding activity typically involves two subunits, a 50-kDa protein (17, 31, 45) and a 65-kDa protein (63,72). NF-KB p50 and NF-KB p65 share a highly homologous 300-residue N-terminal region. This region is also found in the products of the proto-oncogene c-rel and of the dorsal maternal effect gene of Drosophila mela...

NF‐κB synergizes with NF‐AT and NF‐IL6 in activation of the IL‐4 gene in T cells

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