4kv4 | pdb_00004kv4
Brd4 Bromodomain 2 in Complex with Acetylated Rel Peptide
Structural highlights
FunctionTF65_HUMAN NF-kappa-B is a pleiotropic transcription factor present in almost all cell types and is the endpoint of a series of signal transduction events that are initiated by a vast array of stimuli related to many biological processes such as inflammation, immunity, differentiation, cell growth, tumorigenesis and apoptosis. NF-kappa-B is a homo- or heterodimeric complex formed by the Rel-like domain-containing proteins RELA/p65, RELB, NFKB1/p105, NFKB1/p50, REL and NFKB2/p52 and the heterodimeric p65-p50 complex appears to be most abundant one. The dimers bind at kappa-B sites in the DNA of their target genes and the individual dimers have distinct preferences for different kappa-B sites that they can bind with distinguishable affinity and specificity. Different dimer combinations act as transcriptional activators or repressors, respectively. NF-kappa-B is controlled by various mechanisms of post-translational modification and subcellular compartmentalization as well as by interactions with other cofactors or corepressors. NF-kappa-B complexes are held in the cytoplasm in an inactive state complexed with members of the NF-kappa-B inhibitor (I-kappa-B) family. In a conventional activation pathway, I-kappa-B is phosphorylated by I-kappa-B kinases (IKKs) in response to different activators, subsequently degraded thus liberating the active NF-kappa-B complex which translocates to the nucleus. NF-kappa-B heterodimeric p65-p50 and p65-c-Rel complexes are transcriptional activators. The NF-kappa-B p65-p65 complex appears to be involved in invasin-mediated activation of IL-8 expression. The inhibitory effect of I-kappa-B upon NF-kappa-B the cytoplasm is exerted primarily through the interaction with p65. p65 shows a weak DNA-binding site which could contribute directly to DNA binding in the NF-kappa-B complex. Associates with chromatin at the NF-kappa-B promoter region via association with DDX1.[1] [2] [3] [4] [5] [6] Publication Abstract from PubMedAcetylation of the RelA subunit of NF-kappaB at lysine-310 regulates the transcriptional activation of NF-kappaB target genes and contributes to maintaining constitutively active NF-kappaB in tumors. Bromodomain-containing factor Brd4 has been shown to bind to acetylated lysine-310 (AcLys310) and to regulate the transcriptional activity of NF-kappaB, but the role of this binding in maintaining constitutively active NF-kappaB in tumors remains elusive. In this study, we demonstrate the structural basis for the binding of bromodomains (BDs) of bromodomain-containing protein 4 (Brd4) to AcLys310 and identify the BD inhibitor JQ1 as an effective small molecule to block this interaction. JQ1 suppresses TNF-alpha-mediated NF-kappaB activation and NF-kappaB-dependent target gene expression. In addition, JQ1 inhibits the proliferation and transformation potential of A549 lung cancer cells and suppresses the tumorigenicity of A549 cells in severe combined immunodeficiency mice. Furthermore, we demonstrate that depletion of Brd4 or treatment of cells with JQ1 induces the ubiquitination and degradation of the constitutively active nuclear form of RelA. Our results identify a novel function of Brd4 in maintaining the persistently active form of NF-kappaB found in tumors, and they suggest that interference with the interaction between acetylated RelA and Brd4 could be a potential therapeutic approach for the treatment of NF-kappaB-driven cancer.Oncogene advance online publication, 20 May 2013; doi:10.1038/onc.2013.179. Brd4 maintains constitutively active NF-kappaB in cancer cells by binding to acetylated RelA.,Zou Z, Huang B, Wu X, Zhang H, Qi J, Bradner J, Nair S, Chen LF Oncogene. 2013 May 20. doi: 10.1038/onc.2013.179. PMID:23686307[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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