Functional and Physical Associations between NF-κB and C/EBP Family Members: a Rel Domain-bZIP Interaction

Abstract

NF-kappa B and C/EBP represent distinct families of transcription factors that target unique DNA enhancer elements. The heterodimeric NF-kappa B complex is composed of two subunits, a 50- and a 65-kDa protein. All members of the NF-kappa B 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 consist of several related proteins, C/EBP alpha, C/EBP beta, C/EBP gamma, and C/EBP delta, that form homodimers and that form heterodimers with each other. We now demonstrated the unexpected cross-coupling of members of the NF-kappa B family three members of the C/EBP family. NF-kappa B p65, p50, and Rel functionally synergize with C/EBP alpha, C/EBP beta, and C/EBP delta. This cross-coupling results in the inhibition of promoters with kappa B enhancer motifs and in the synergistic stimulation of promoters with C/EBP binding sites. These studies demonstrate that NF-kappa B 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-kappa B. The cross-coupling of NF-kappa B with C/EBP highlights a mechanism of gene regulation involving an interaction between distinct transcription factor families.

Ubiquitin Specific Protease USP48 Destabilizes NF-κB/p65 in Retinal Pigment Epithelium Cells

“…This trimming activity selectively rescues target nuclear proteins from proteasomal degradation and depends on the regulatory interactors in response to stimulation [ 17 ]. Reported USP48 substrates include histone H2A, Gli1, Aurora B and p65 [ 14 , 17 , 18 , 19 , 20 ].…”

“…The newly synthesized nuclear IκBα acts both at the nuclear level, by removing the NF-κB/p65 complex from the DNA and terminating its transcriptional activity, and at the cytosolic level, by transporting p65 back to the cytoplasm. In the nuclei, NF-κB transcriptional activity is further modulated by the crosstalk with other transcription factors resulting in either synergistic (e.g., AP-1) or antagonistic (e.g., cEBP/β) effects [ 8 , 20 ]. Moreover, the differential binding kinetics of p65 with different importin/exportin proteins and the modulation by post-translational modifications provide further mechanisms of NF-κB activity regulation, overall determining the extent of nuclear translocation of p65 [ 21 , 22 , 23 , 24 ].…”

The mechanism of microglia-mediated immune inflammation in ischemic stroke and the role of natural botanical components in regulating microglia: A review

“…(2) cAMP response element binding protein (CREB): CREB cooperates with C/EBPβ and amplifies the expression of M2 phenotype-specific genes such as IL-10 and Arg1, promoting tissue repair ( 148 ), while the expression of M1 phenotype genes encoding pro-inflammatory molecules is also regulated by C/EBPβ ( 149 ). The dual role of C/EBPβ in regulating gene expression of M1 and M2 phenotypes may result from the competition between CREB and NF-κB for binding to C/EBP ( 148 , 150 ). (3) Interferon regulatory factor-3 (IRF-3): In response to TLR activation, PI3K/Akt signaling initiates phosphorylated IRF-3.…”

Emerging functions of C/EBPβ in breast cancer

“…Early studies indicated that C/EBPβ binds to an IL-1 response element in the IL-6 promoter to drive IL-6 and IL-8 transcription. C/EBPβ and other C/EBP family members can directly interact with the Rel homology domain between NF-κB subunits p50, p65 and c-Rel, stabilizing NF-κB, leading to synergistic transcriptional activation of IL-6 and IL-8 ( 69 , 70 ). C/EBPβ can also positively regulate NF-κB by binding and inactivating IκBα, the canonical inhibitor of NF-κB ( 71 ).…”