Publication: The NF-kB-mediated control of ROS and JNK signaling
Authors
Bubici, C. ; Papa, S. ; Pham, C.G. ; Zazzeroni, F. ; Franzoso, G.
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Publisher
Murcia : F. Hernández
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DOI
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info:eu-repo/semantics/article
Description
Abstract
NF-kB/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-kB
antagonizes programmed cell death (PCD) induced by
the proinflammatory cytokine tumor necrosis factor
(TNF)a and plays an important role in immunity,
lymphopoiesis, osteogenesis, tumorigenesis and radioand
chemo-resistance in cancer. With regard to TNFa,
the NF-kB-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, Gadd45ß/Myd118. Notably, NF-
kB also blunts accumulation of reactive oxygen species
(ROS), which themselves are pivotal elements for
induction of PCD by TNFa, and this suppression of
ROS formation mediates an additional protective activity
recently ascribed to NF-kB. The antioxidant activity of
NF-kB 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-kB controls proapoptotic JNK
signaling triggered by TNFa. These findings might
enable the development of new, more targeted
approaches to treatment of diseases sustained by a
deregulated activity of NF-kB, including some cancers
and chronic inflammatory conditions.
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