The NF-kappaB-mediated control of ROS and JNK signaling.
NF-kappaB/Rel transcription factors are best known for their roles in innate and adaptive immunity and inflammation. They also play a central role in promoting cell survival. This latter activity of NF-kappaB antagonizes programmed cell death (PCD) induced by the proinflammatory cytokine tumor necrosis factor (TNF)alpha and plays an important role in immunity, lymphopoiesis, osteogenesis, tumorigenesis and radio- and chemoresistance in cancer. With regard to TNFalpha, the NF-kappaB-mediated inhibition of PCD seems to involve an attenuation of the c-Jun-N-terminal kinase (JNK) cascade mediated through the induction of select downstream targets such as the caspase inhibitor XIAP, the zinc-finger protein A20, and the inhibitor of the MKK7/JNKK2 kinase, Gadd45beta/Myd118. Notably, NF-kappaB also blunts accumulation of reactive oxygen species (ROS), which themselves are pivotal elements for induction of PCD by TNFalpha, and this suppression of ROS formation mediates an additional protective activity recently ascribed to NF-kappaB. The antioxidant activity of NF-kappaB has been shown to depend upon upregulation of both Ferritin heavy chain (FHC)--a component of Ferritin, the primary iron-storage protein complex found in cells--and of the mitochondrial enzyme Mn++ superoxide dismutase (Mn-SOD). Indeed, the inductions of Mn-SOD and FHC represent another important means through which NF-kappaB controls proapoptotic JNK signaling triggered by TNFalpha. These findings might enable the development of new, more targeted approaches to treatment of diseases sustained by a deregulated activity of NF-kappaB, including some cancers and chronic inflammatory conditions.
Bubici
C
C
The Ben May Institute for Cancer Research, The University of Chicago, Chicago, IL 60637, USA.
Papa
S
S
Pham
C G
CG
Zazzeroni
F
F
Franzoso
G
G
D000818:Animals; D000975:Antioxidants / Q000502:physiology; D017209:Apoptosis / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000502:physiology; D005293:Ferritins / Q000502:physiology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D016328:NF-kappa B / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000502:physiology; D013482:Superoxide Dismutase / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D000975:Antioxidants; D051017:Apoptosis Regulatory Proteins; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; D005293:Ferritins; D013482:Superoxide Dismutase; D048031:JNK Mitogen-Activated Protein Kinases