title: Gadd45 beta mediates the NF-kappa B suppression of JNK signalling by targeting MKK7/JNKK2.
abstract: NF-kappa B/Rel transcription factors control apoptosis, also known as programmed cell death. This control is crucial for oncogenesis, cancer chemo-resistance and for antagonizing tumour necrosis factor alpha (TNFalpha)-induced killing. With regard to TNFalpha, the anti-apoptotic activity of NF-kappa B involves suppression of the c-Jun N-terminal kinase (JNK) cascade. Using an unbiased screen, we have previously identified Gadd45 beta/Myd118, a member of the Gadd45 family of inducible factors, as a pivotal mediator of this suppressive activity of NF-kappa B. However, the mechanisms by which Gadd45 beta inhibits JNK signalling are not understood. Here, we identify MKK7/JNKK2--a specific and essential activator of JNK--as a target of Gadd45 beta, and in fact, of NF-kappa B itself. Gadd45 beta binds to MKK7 directly and blocks its catalytic activity, thereby providing a molecular link between the NF-kappa B and JNK pathways. Importantly, Gadd45 beta is required to antagonize TNFalpha-induced cytotoxicity, and peptides disrupting the Gadd45 beta/MKK7 interaction hinder the ability of Gadd45 beta, as well as of NF-kappa B, to suppress this cytotoxicity. These findings establish a basis for the NF-kappa B control of JNK activation and identify MKK7 as a potential target for anti-inflammatory and anti-cancer therapy.
authors.affiliation: The Gwen Knapp Center for Lupus and Immunology Research, and The Ben May Institute for Cancer Research, The University of Chicago, 924 East 57th Street, Chicago, IL 60637, USA.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Papa
authors.forename: Francesca
authors.initials: F
authors.lastname: Zazzeroni
authors.forename: Concetta
authors.initials: C
authors.lastname: Bubici
authors.forename: Shanthi
authors.initials: S
authors.lastname: Jayawardena
authors.forename: Kellean
authors.initials: K
authors.lastname: Alvarez
authors.forename: Shuji
authors.initials: S
authors.lastname: Matsuda
authors.forename: Dung U
authors.initials: DU
authors.lastname: Nguyen
authors.forename: Can G
authors.initials: CG
authors.lastname: Pham
authors.forename: Andreas H
authors.initials: AH
authors.lastname: Nelsbach
authors.forename: Tiziana
authors.initials: T
authors.lastname: Melis
authors.forename: Enrico
authors.initials: E
authors.lastname: De Smaele
authors.forename: Wei-Jen
authors.initials: WJ
authors.lastname: Tang
authors.forename: Luciano
authors.initials: L
authors.lastname: D'Adamio
authors.forename: Guido
authors.initials: G
authors.lastname: Franzoso
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism*; D017209:Apoptosis / Q000502:physiology; D002478:Cells, Cultured; D004789:Enzyme Activation; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D048688:MAP Kinase Kinase 7; D051379:Mice; D018345:Mice, Knockout; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism*; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D016415:Sequence Alignment; D015398:Signal Transduction / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000097642:GADD45 Proteins
chemical_list: D000943:Antigens, Differentiation; D048031:JNK Mitogen-Activated Protein Kinases; D048688:MAP Kinase Kinase 7; D020929:Mitogen-Activated Protein Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B; D010455:Peptides; D014409:Tumor Necrosis Factor-alpha; C086470:GADD45B protein, human; D000097642:GADD45 Proteins; C490125:Gadd45b protein, mouse; C482569:MAP2K7 protein, human; C482570:Map2k7 protein, mouse