Nuclear Factor Kappa B Signaling Complexes in Acute Inflammation (original) (raw)
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The complexity of NF-κB signaling in inflammation and cancer
Molecular Cancer, 2013
The NF-κB family of transcription factors has an essential role in inflammation and innate immunity. Furthermore, NF-κB is increasingly recognized as a crucial player in many steps of cancer initiation and progression. During these latter processes NF-κB cooperates with multiple other signaling molecules and pathways. Prominent nodes of crosstalk are mediated by other transcription factors such as STAT3 and p53 or the ETS related gene ERG. These transcription factors either directly interact with NF-κB subunits or affect NF-κB target genes. Crosstalk can also occur through different kinases, such as GSK3-β, p38, or PI3K, which modulate NF-κB transcriptional activity or affect upstream signaling pathways. Other classes of molecules that act as nodes of crosstalk are reactive oxygen species and miRNAs. In this review, we provide an overview of the most relevant modes of crosstalk and cooperativity between NF-κB and other signaling molecules during inflammation and cancer.
Crosstalk of reactive oxygen species and NF-κB signaling
Cell Research, 2010
NF-κB proteins are a family of transcription factors that are of central importance in inflammation and immunity. NF-κB also plays important roles in other processes, including development, cell growth and survival, and proliferation, and is involved in many pathological conditions. Reactive Oxygen Species (ROS) are created by a variety of cellular processes as part of cellular signaling events. While certain NF-κB-regulated genes play a major role in regulating the amount of ROS in the cell, ROS have various inhibitory or stimulatory roles in NF-κB signaling. Here we review the regulation of ROS levels by NF-κB targets and various ways in which ROS have been proposed to impact NF-κB signaling pathways.
A Beginner's Guide to NF-κB Signaling Pathways
Annals of the New York Academy of Sciences, 2004
A BSTRACT : Nuclear factor B (NF-B) belongs to a family of heterodimeric transcription factors that play a key role in inflammatory and stress responses as well as in tumor cell resistance to apoptosis. These effects are due to the NF-B-dependent transcription of many proinflammatory and antiapoptotic genes, whose products ensure various cell responses to environmental conditions. The signal transduction pathways leading to NF-B activation are well characterized, and the different steps implicated in these pathways involve proteins that could constitute targets for NF-B inhibition. Several inhibitors aiming to prevent NF-B activity and thus the transcription of target genes are studied, and a few compounds seem particularly promising. We try here to summarize the advantages that can issue from various studies on NF-B.
Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 2008
Constitutively activated NF-κB occurs in many inflammatory and tumor tissues. Does it interfere with anti-inflammatory or anti-tumor signaling pathway? Here, we report that NF-κB p65 subunit repressed the Nrf2-antioxidant response element (ARE) pathway at transcriptional level. In the cells where NF-κB and Nrf2 were simultaneously activated, p65 unidirectionally antagonized the transcriptional activity of Nrf2. In the p65overexpressing cells, the ARE-dependent expression of heme oxygenase-1 was strongly suppressed. However, p65 inhibited the ARE-driven gene transcription in a way that was independent of its own transcriptional activity. Two mechanisms were found to coordinate the p65-mediated repression of ARE: (1) p65 selectively deprives CREB binding protein (CBP) from Nrf2 by competitive interaction with the CH1-KIX domain of CBP, which results in inactivation of Nrf2. The inactivation depends on PKA catalytic subunit-mediated phosphorylation of p65 at S276. (2) p65 promotes recruitment of histone deacetylase 3 (HDAC3), the corepressor, to ARE by facilitating the interaction of HDAC3 with either CBP or MafK, leading to local histone hypoacetylation. This investigation revealed the participation of NF-κB p65 in the negative regulation of Nrf2-ARE signaling, and might provide a new insight into a possible role of NF-κB in suppressing the expression of anti-inflammatory or anti-tumor genes.
International Journal of Pharmacy and Pharmaceutical Sciences, 2024
NF-κB is a vital transcription factor that responds to diverse stimuli like cytokines, infections, and stress. It forms different dimers, binds to specific DNA sequences, and regulates gene expression. It operates through two pathways: canonical (for inflammation and immunity) and non-canonical (for specific processes). These pathways tightly control activity of NF-κB and impacting gene expression. Aberrant NF-κB activation is linked to cancer and other diseases, making it a potential therapeutic target. This review explores the role of NF-κB in disease and its therapeutic potential in various conditions. Intricate signal transduction processes lead to NF-κB activation by phosphorylating IκB proteins, allowing NF-κB dimers to enter the nucleus and influence gene expression. This dynamic regulation involves co-activators and interactions with other transcription factors, shaping complex gene expression programs. Understanding the multifaceted functions off NF-κB is crucial as its deregulation is associated with a range of diseases, including cancer, autoimmune disorders, and inflammatory conditions. Exploring recent studies offers insights into potential therapeutic strategies aimed at modulating NF-κB activity to restore health and combat various pathological conditions. This Comprehensive review is based on the role of NF-κB in disease pathogenesis and therapeutic implications.
Activation of Nrf2-antioxidant signaling attenuates NFκB-inflammatory response and elicits apoptosis
Biochemical Pharmacology, 2008
Oxidative stress has been implicated in the etiology of neurodegenerative disease, cancer and aging. Indeed, the reactive oxygen and nitrogen species generated by inflammatory cells that created oxidative stress is thought to be one of the major factor by which chronic inflammation contributes to neoplastic transformation as well as many other diseases. We have recently reported that mice lacking nuclear factor-erythroid 2-related factor 2 (Nrf2) are more susceptibility to dextran sulfate sodium (DSS)-induced colitis and colorectal carcinogenesis. Nrf2 is a basic leucine zipper redoxsensitive transcriptional factor that plays a center role in ARE (antioxidant response element)mediated induction of phase II detoxifying and antioxidant enzymes. We found that increased susceptibility of Nrf2 deficient mice to DSS-induced colitis and colorectal cancer was associated with decreased expression of antioxidant/phase II detoxifying enzymes in parallel with upregulation of pro-inflammatory cytokines/biomarkers. These findings suggest that Nrf2 may play an important role in defense against oxidative stress possibly by activation of cellular antioxidant machinery as well as suppression of pro-inflammatory signaling pathways. In addition, in vivo and in vitro data generated from our laboratory suggest that many dietary compounds can differentially regulate Nrf2mediated antioxidant/anti-inflammatory signaling pathways as the first line defense or induce apoptosis once the cells have been damaged. In this review, we will summarize our thoughts on the potential cross-talks between Nrf2 and NF-κB pathways. Although the mechanisms involved in the cross-talk between these signaling pathways are still illusive, targeting Nrf2-antioxidative stress signaling is an ideal strategy to prevent or treat oxidative-stress related diseases.
Oxidants Positively or Negatively Regulate Nuclear Factor κB in a Context-dependent Manner
Journal of Biological Chemistry, 2010
Redox-based mechanisms play critical roles in the regulation of multiple cellular functions. NF-B, a master regulator of inflammation, is an inducible transcription factor generally considered to be redox-sensitive, but the modes of interactions between oxidant stress and NF-B are incompletely defined. Here, we show that oxidants can either amplify or suppress NF-B activation in vitro by interfering both with positive and negative signals in the NF-B pathway. NF-B activation was evaluated in lung A549 epithelial cells stimulated with tumor necrosis factor ␣ (TNF␣), either alone or in combination with various oxidant species, including hydrogen peroxide or peroxynitrite. Exposure to oxidants after TNF␣ stimulation produced a robust and long lasting hyperactivation of NF-B by preventing resynthesis of the NF-B inhibitor IB, thereby abrogating the major negative feedback loop of NF-B. This effect was related to continuous activation of inhibitor of B kinase (IKK), due to persistent IKK phosphorylation consecutive to oxidant-mediated inactivation of protein phosphatase 2A. In contrast, exposure to oxidants before TNF␣ stimulation impaired IKK phosphorylation and activation, leading to complete prevention of NF-B activation. Comparable effects were obtained when interleukin-1 was used instead of TNF␣ as the NF-B activator. This study demonstrates that the influence of oxidants on NF-B is entirely context-dependent, and that the final outcome (activation versus inhibition) depends on a balanced inhibition of protein phosphatase 2A and IKK by oxidant species. Our findings provide a new conceptual framework to understand the role of oxidant stress during inflammatory processes.
The role of NF-κB in the regulation of cell stress responses
International Immunopharmacology, 2002
Nuclear factor-nB (NF-nB) is one of the key regulatory molecules in oxidative stress-induced cell activation. NF-nB is normally sequestered in the cytoplasm of nonstimulated cells and must translocate into the nucleus to regulate effector gene expression. A family of inhibitory proteins, InBs, binds to NF-nB and masks its nuclear localization signal domain and therefore controls the translocation of NF-nB. Exposure of cells to extracellular stimuli that perturb redox balance results in rapid phosphorylation, ubiquitination, and proteolytic degradation of InBs. This process frees NF-nB from the NF-nB/InB complexes and enables NF-nB to translocate to the nucleus where it regulates gene transcription. Many effector genes including those encoding cytokines and adhesion molecules are in turn regulated by NF-nB. NF-nB is also an essential component of ionizing radiation (IR)-triggered signal transduction pathways that can lead to cell death or survival. The purpose of this review is to briefly summarize the recent progress in the studies of the role of reactive oxygen species (ROS), cytokines and ionizing radiation in NF-nB activation.
Biochimica et biophysica acta, 2008
Constitutively activated NF-kappaB occurs in many inflammatory and tumor tissues. Does it interfere with anti-inflammatory or anti-tumor signaling pathway? Here, we report that NF-kappaB p65 subunit repressed the Nrf2-antioxidant response element (ARE) pathway at transcriptional level. In the cells where NF-kappaB and Nrf2 were simultaneously activated, p65 unidirectionally antagonized the transcriptional activity of Nrf2. In the p65-overexpressing cells, the ARE-dependent expression of heme oxygenase-1 was strongly suppressed. However, p65 inhibited the ARE-driven gene transcription in a way that was independent of its own transcriptional activity. Two mechanisms were found to coordinate the p65-mediated repression of ARE: (1) p65 selectively deprives CREB binding protein (CBP) from Nrf2 by competitive interaction with the CH1-KIX domain of CBP, which results in inactivation of Nrf2. The inactivation depends on PKA catalytic subunit-mediated phosphorylation of p65 at S276. (2) p65 ...