Gadd45 beta mediates the NF-kappa B suppression of JNK signalling by targeting MKK7/JNKK2.
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.
Papa
Salvatore
S
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.
Zazzeroni
Francesca
F
Bubici
Concetta
C
Jayawardena
Shanthi
S
Alvarez
Kellean
K
Matsuda
Shuji
S
Nguyen
Dung U
DU
Pham
Can G
CG
Nelsbach
Andreas H
AH
Melis
Tiziana
T
De Smaele
Enrico
E
Tang
Wei-Jen
WJ
D'Adamio
Luciano
L
Franzoso
Guido
G
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
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