Linking JNK signaling to NF-kappaB: a key to survival.
In addition to marshalling immune and inflammatory responses, transcription factors of the NF-kappaB family control cell survival. This control is crucial to a wide range of biological processes, including B and T lymphopoiesis, adaptive immunity, oncogenesis and cancer chemoresistance. During an inflammatory response, NF-kappaB activation antagonizes apoptosis induced by tumor necrosis factor (TNF)-alpha, a protective activity that involves suppression of the Jun N-terminal kinase (JNK) cascade. This suppression can involve upregulation of the Gadd45-family member Gadd45beta/Myd118, which associates with the JNK kinase MKK7/JNKK2 and blocks its catalytic activity. Upregulation of XIAP, A20 and blockers of reactive oxygen species (ROS) appear to be important additional means by which NF-kappaB blunts JNK signaling. These recent findings might open up entirely new avenues for therapeutic intervention in chronic inflammatory diseases and certain cancers; indeed, the Gadd45beta-MKK7 interaction might be a key target for such intervention.
The Ben May Institute for Cancer Research, The University of Chicago, 924 East 57th Street, Chicago, IL 60637, USA.
Salvatore
S
Papa
Francesca
F
Zazzeroni
Can G
CG
Pham
Concetta
C
Bubici
Guido
G
Franzoso
D000818:Animals; D017209:Apoptosis; D002470:Cell Survival; D004247:DNA / Q000737:chemistry; D019143:Evolution, Molecular; D006801:Humans; D007249:Inflammation; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D048670:MAP Kinase Kinase 4; D048688:MAP Kinase Kinase 7 / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism; D017382:Reactive Oxygen Species; D015398:Signal Transduction; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation; D000097642:GADD45 Proteins
D004247:DNA; D047908:Intracellular Signaling Peptides and Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D048688:MAP Kinase Kinase 7; D020929:Mitogen-Activated Protein Kinase Kinases; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D000097642:GADD45 Proteins; C482569:MAP2K7 protein, human