Cross-coupling of the NF-kappa B p65 and Fos/Jun transcription factors produces potentiated biological function.

Abstract

NF‐kappa B and AP‐1 represent distinct mammalian transcription factors that target unique DNA enhancer elements. The heterodimeric NF‐kappa B complex is typically composed of two DNA binding subunits, NF‐kappa B p50 and NF‐kappa B p65, which share structural homology with the c‐rel proto‐oncogene product. Similarly, the AP‐1 transcription factor complex is comprised of dimers of the c‐fos and c‐jun proto‐oncogene products or of closely related proteins. We now demonstrate that the bZIP regions of c‐Fos and c‐Jun are capable of physically interacting with NF‐kappa B p65 through the Rel homology domain. This complex of NF‐kappa B p65 and Jun or Fos exhibits enhanced DNA binding and biological function via both the kappa B and AP‐1 response elements including synergistic activation of the 5′ long terminal repeat of the human immunodeficiency virus type 1. These findings support a combinatorial mechanism of gene regulation involving the unexpected cross‐coupling of two different classes of transcription factors to form novel protein complexes exhibiting potentiated biological activity.

Expression of human p53 requires synergistic activation of transcription from the p53 promoter by AP-1, NF-κB and Myc/Max

“…Moreover, the e cient suppression of transcription by deletion of the AP-1 motif or the mutation of one of the other motifs documents a cooperativity in the transactivation from the hp53 promoter between AP-1, NF-kB, and Myc/Max. A transcriptional cooperativity that involves AP-1 and NF-kB has also been described for promoters of other genes like MHC class I (H-2K b , Brockmann et al, 1996), E-Selectin (Kaszubska et al, 1993), I-kBa (Kralova et al, 1996), IL-8 (Yasumoto et al, 1992) and IFNb (Du W et al, 1993), either involving direct (Stein et al, 1993) or indirect (Gerritsen et al, 1997) physical interaction of the respective transcription factors. Figure 3 Binding of nuclear proteins to the AP-1 motif in the human p53-promoter.…”

Redox signalling by transcription factors NF-κB and AP-1 in lymphocytes

“…Some of these factors can physically interact among each other when bound to DNA and thereby synergistically promote their DNA-binding and transactivating activity. NF-KB was found to interact directly with AP-l subunits [58]. NF-ATp, an NF-KB/Rel-related transcription factor activated by the calcium-dependent phosphatase calcineurin, also binds AP-l and recruits the factor to DNA [59].…”

Physical and functional cooperation between AP-1 and β-catenin for the regulation of TCF-dependent genes

“…Fos and Jun proteins, the main AP-1 constituents, are able to modulate gene transcription by a mechanism independent from their binding to DNA, implying protein/protein interactions. For example, synergistic or antagonistic transcriptional effects related to AP-1 protein cooperation with p65 nuclear factor kappa B (NFkB) or Smad proteins have been described by us and other groups (Stein et al, 1993;Peron et al, 2001;Rahmani et al, 2001;Verrecchia et al, 2001;Ferrigno et al, 2002). In this study, we show that b-catenin directly interacts with c-Jun and c-Fos proteins, both in vitro and in vivo, and that overexpression of c-Jun and c-Fos potentiates the transactivation of b-catenin target genes, such as cyclin D1 and c-myc, by a mechanism dependent on the TCF-binding element (TBE) and independent from the AP-1 site.…”