1,720,969 research outputs found
Oxygen JNKies: phosphatases overdose on ROS
No full textProinflammatory cytokine TNFalpha triggers cell death by inducing reactive oxygen species (ROS). These then inflict cytotoxicity through downstream activation of the JNK MAPK cascade. Yet the mechanisms by which ROS trigger JNK signaling have remained elusive. In a recent issue of Cell, Kamata et al. now provide one such mechanism
NF-kappaB meets ROS: an 'iron-ic' encounter
No full textSince becoming abundant in the atmosphere approximately 2.3 billion years ago, oxygen has been a defining element for life on our planet. One needs not be a biologist to know the importance of oxygen for sustaining life – termed in fact ‘aerobic’ life. Our body is built around the need to maximize exploitation of oxygen for the production of energy. The respiratory and cardiovascular systems are exemplary illus- trations of this need. Like all good things, however, oxygen can also be extremely harmful. Its original accumulation on Earth caused the extinction of most existing life forms, defenseless against oxidative damage. Even a layperson is aware of this potential toxicity of oxygen. Indeed, nowadays antioxidants are among the most heavily advertised dietary supplements on the market. Yet, it would surprise most to know that the potent reactivity of oxygen and its products – so- called reactive oxygen species (ROS) – is purposefully used by nature to transduce signals that actively trigger cell suicide or programmed cell death (PCD), as well as other biological responses.
One pathway that seems to fully exploit this reactivity of ROS for inflicting cell death is that initiated by TNFa engagement of TNF-R1, a pathway that plays a central role in immunity, inflammation, cell growth, cell death and differentiation.1–3 This pathway is also crucial for pathogen- esis of human diseases such as cancer and chronic inflammatory conditions, including rheumatoid arthritis (RA) and inflammatory bowel disease (IBD).1,3,4 Not surprisingly, it has been the subject of intense investigation for over one century.1 TNFa-induced killing is antagonized by activation of NF-kB-family transcription factors3,4 – which act as master coordinators of immune and inflammatory responses.4 The prosurvival activity of NF-kB is also crucial for lymphocyte development, tumorigenesis and cancer chemoresistance.4,5 In recent years, remarkable progress has been made in our understanding of the mechanisms governing TNFa-induced death and NF-kB-mediated survival.3,4 As it turns out, ROS have now taken center stage in the intricate multitude of players that control cell fate downstream of TNF-R1, as they appear to be at an obligatory crossroads of the opposing pathways for life and death elicited by stimulation of this receptor. Indeed, now there is hope that this new under-
standing of TNF-R-induced pathways may lead to the development of new approaches for treatment of widespread human diseases
The NF-kappaB-mediated control of ROS and JNK signaling
No full textNF-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
In the Crosshairs: NF-κB Targets the JNK Signaling Cascade.
No full textNF-κB/Rel transcription factors are well-known for their roles in the regulation of inflammation and immunity. NF-κB also blocks programmed cell death (PCD) or apoptosis triggered by proinflammatory cytokine, tumor necrosis factor (TNF)α. Through transcriptional induction of distinct subsets of cyto-protective target genes, NF-κB inhibits the execution of apoptosis activated by this cytokine. This protective action is mediated, in part, by factors (such as A20, GADD45β, and XIAP) that downregulate the pro-apoptotic c-Jun-N-terminal (JNK) pathway. A suppression of reactive oxygen species (ROS), which are themselves major cell death-inducing elements activated by TNFα, is an additional protective function recently ascribed to NF-κB. This function of NF-κB involves an induction of mitochondrial anti-oxidant enzyme, manganese superoxide dismutase (Mn-SOD), and a control of cellular iron availability through upregulation of Ferritin heavy chain – one of two subunits of Ferritin, the major iron storage protein complex of the cell. An emerging view of NF-κB is that, while integrated, its actions in immunity and in promoting cell survival are executed through upregulation of distinct subsets of target genes. Thus, these inducible blockers of apoptosis may provide potential new targets to inhibit specific functions of NF-κB. In the future, this might allow for a better treatment of complex human diseases involving dysregulated NF-κB activity, including chronic inflammatory conditions and cancer
A method for isolating prosurvival targets of NF-kappaB/Rel transcription factors
No full textNF-KappaB/Rel transcription factors are critical regulators of immunity, inflammation, development, and cell survival. Activation of NF-KB inhibits programmed cell death (PCD) triggered by tumor necrosis factor alpha (TNFalpha) and several other stimuli. The prosurvival activity of NF-KB is also crucial to lymphopoiesis, neuroprotection, tumorigenesis, and cancer chemoresistance. The characterization of the downstream targets that mediate the prosurvival activity of NF-KB is therefore a topic of intense investigation. Early screens aimed at identifying these genes were mainly based on expression criteria and so were poised to only isolate genes already known to have protective effects. Here, we describe a new method for the identification of these genes, whereby expression libraries are screened for their ability to halt PCD in NF-KB-deficient cells. This complementation approach provides substantial advantages over other approaches, as it enables functional assessment of isolated genes without any preconceived notion about their sequence or presumed role. Expression libraries are generated from cells that are resistant to TNFalpha-induced cytotoxicity and are then enriched in prosurvival genes upon selection with TNFa in NF-kappaB/RelA-null cells, which are highly susceptible instead to this cytotoxicity. Upon enrichment, libraries are screened through a randomized two-step approach, whereby cDNAs are first tested for cytoprotective function and then for differential expression in NF-kappaB-proficient and NF-KappaB-deficient cells
Upregulation of Twist-1 by NF-{kappa}B Blocks Cytotoxicity Induced by Chemotherapeutic Drugs
No full textNF-kappaB/Rel transcription factors are central to controlling programmed cell death (PCD). Activation of NF-kappaB blocks PCD induced by numerous triggers, including ligand engagement of tumor necrosis factor receptor (TNF-R) family receptors. The protective activity of NF-kappaB is also crucial for oncogenesis and cancer chemoresistance. Downstream of TNF-Rs, this activity of NF-kappaB has been linked to the suppression of reactive oxygen species and the c-Jun-N-terminal-kinase (JNK) cascade. The mechanism by which NF-kappaB inhibits PCD triggered by chemotherapeutic drugs, however, remains poorly understood. To understand this mechanism, we sought to identify unrecognized protective genes that are regulated by NF-kappaB. Using an unbiased screen, we identified the basic-helix-loop-helix factor Twist-1 as a new mediator of the protective function of NF-kappaB. Twist-1 is an evolutionarily conserved target of NF-kappaB, blocks PCD induced by chemotherapeutic drugs and TNF-alpha in NF-kappaB-deficient cells, and is essential to counter this PCD in cancer cells. The protective activity of Twist-1 seemingly halts PCD independently of interference with cytotoxic JNK, p53, and p19(ARF) signaling, suggesting that it mediates a novel protective mechanism activated by NF-kappaB. Indeed, our data indicate that this activity involves a control of inhibitory Bcl-2 phosphorylation. The data also suggest that Twist-1 and -2 play an important role in NF-kappaB-dependent chemoresistance
The NF-kappaB-mediated control of the JNK cascade in the antagonism of programmed cell death in health and disease
No full textNF-kappaB/Rel transcription factors have recently emerged as crucial regulators of cell survival. Activation of NF-kappaB antagonizes programmed cell death (PCD) induced by tumor necrosis factor-receptors (TNF-Rs) and several other triggers. This prosurvival activity of NF-kappaB participates in a wide range of biological processes, including immunity, lymphopoiesis and development. It is also crucial for pathogenesis of various cancers, chronic inflammation and certain hereditary disorders. This participation of NF-kappaB in survival signaling often involves an antagonism of PCD triggered by TNF-R-family receptors, and is mediated through a suppression of the formation of reactive oxygen species (ROS) and a control of sustained activation of the Jun-N-terminal kinase (JNK) cascade. Effectors of this antagonistic activity of NF-kappaB on this ROS/JNK pathway have been recently identified. Indeed, further delineating the mechanisms by which NF-kappaB promotes cell survival might hold the key to developing new highly effective therapies for treatment of widespread human diseases
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