IκB kinases: key regulators of the NF-κB pathway

Yamamoto, Yumi; Gaynor, Richard B.

doi:10.1016/j.tibs.2003.12.003

Cited by 599 publications

(431 citation statements)

References 71 publications

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“…This process releases and allows nuclear translocation and transcriptional activation of NFkB. 16,48 Activated NF-kB induces transcription of target genes such as Bcl-2 21 and MMP-9. 17,18 In agreement with these data, Bcl-2 appears to have a relevant role in RES-induced apoptosis in MCF-7, not only because its expression decreased in cells undergoing apoptosis but also because MCF-7-Bcl-2 cells, transfected to overexpress this protein, were insensitive to apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…21 To analyze if the effect of RES on Bcl-2 protein levels could be related to decreased NF-kB activity, EMSA experiments were performed using nuclear extracts from MCF-7 cells and a fragment of DNA containing the canonical consensus sequence for this factor (Fig. 2).…”

Section: Res-induced Apoptosis Is Related To Inhibition Of Nf-kb Actimentioning

confidence: 99%

“…Growth factors increase the activity of IKKs, which phosphorylate and target I-kB for proteosomal degradation, thus releasing and allowing NF-kB to enter the nucleus and induce gene expression. 21 In dendritic and mouse embryo fibroblast cells, IKK activity is regulated by the PI3K pathway through PKB/ AKT, implying that PI3K activation leads to increased NF-kB transcription 22,23 and to reduced apoptosis. 24 NF-kB activity is also regulated by calcium-dependent cysteine proteases (calpains).…”

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Resveratrol‐induced apoptosis in MCF‐7 human breast cancer cells involves a caspase‐independent mechanism with downregulation of Bcl‐2 and NF‐κB

Pozo‐Guisado

Merino

Mulero‐Navarro

et al. 2005

Intl Journal of Cancer

209

143

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Resveratrol (RES), a chemopreventive molecule, inhibits the proliferation of tumor cells of different etiologies. We previously showed that RES alters the cell cycle and induces apoptosis in MCF-7 breast tumor cells by interfering with the estrogen receptor (ERa)-dependent phosphoinositide 3-kinase (PI3K) pathway. Here, we analyzed signaling downstream of PI3K, to understand the mechanisms of RES-induced apoptosis. Apoptotic death by RES in MCF-7 was mediated by Bcl-2 downregulation since overexpression of this protein abolished apoptosis. Decreased Bcl-2 levels were not related to cytochrome c release, activation of caspases 3/8 or poly(ADP-ribose) polymerase proteolysis. However, RES decreased mitochondrial membrane potential and increased reactive oxygen species and nitric oxide production. NF-kB, a regulator of Bcl-2 expression, and calpain protease activity, a regulator of NF-kB, were both inhibited by RES. The patterns for NFkB and calpain activities followed that of PI3K and were inhibited by LY294002. NF-kB inhibition coincided with diminished MMP-9 activity and cell migration. These data suggest that RES-induced apoptosis in MCF-7 could involve an oxidative, caspase-independent mechanism, whereby inhibition of PI3K signaling converges to Bcl-2 through NF-kB and calpain protease activity. Therefore, Bcl-2 and NF-kB could be considered potential targets for the chemopreventive activity of RES in estrogen-responsive tumor cells. ' 2005 Wiley-Liss, Inc.Key words: resveratrol; caspase; Bcl-2; NF-kB; apoptosis Among natural compounds with beneficial effects on human health, RES (3,4 0 ,5-trihydroxystilbene) has attracted considerable interest. This molecule, present at relevant concentrations in red wine, 1 has been associated with a lower incidence of cardiovascular disease. Different studies have also suggested a beneficial effect of RES in cancer since it inhibits proliferation and promotes death in tumor cell lines of different origins, 2-4 and, in vivo, suppresses the formation of skin 5 and mammary gland 6 tumors in rodent models of carcinogenesis.We, as well as other laboratories, have found that the ability of RES to inhibit cell viability and proliferation in the human breast cancer cell lines MCF-7 and MDA-MB-231 was unrelated to ERa status. 7,8 However, apoptotic cell death was present only in ERapositive MCF-7 and involved cell-specific regulation of the G 1 /S and G 2 /M transitions of the cell cycle. 2,8 RES properties are related to ERa since this compound has estrogenic or antiestrogenic activities depending on its concentration and the phenotype of the target cell. 9,10 ERa, in addition to its nuclear role as a transcription factor, is involved in regulating the PI3K pathway, which controls cell growth, proliferation and apoptosis. [11][12][13] In MCF-7 cells, RES induced a biphasic pattern of PI3K activity that increased at low concentrations and decreased at high concentrations. Activation of downstream PI3K effectors PKB/AKT and GSK-3 closely followed the pattern of PI3K activity. 14 The ...

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Section: Discussionmentioning

confidence: 99%

Section: Res-induced Apoptosis Is Related To Inhibition Of Nf-kb Actimentioning

confidence: 99%

mentioning

confidence: 99%

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Resveratrol‐induced apoptosis in MCF‐7 human breast cancer cells involves a caspase‐independent mechanism with downregulation of Bcl‐2 and NF‐κB

Pozo‐Guisado

Merino

Mulero‐Navarro

et al. 2005

Intl Journal of Cancer

209

143

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“…3 Research from the past 20 years revealed that three major NF-kB activating pathways can be distinguished. 2,4,5 In the first canonical pathway (Figure 1), the prototypical NF-kB dimer RelA/p50 is activated upon release from its inhibitor IkBa through action of the classical IkB kinase (IKK) complex. Signal-induced activation of the IKK signalosome, consisting of two kinases (IKKa and IKKb) and a regulatory scaffolding subunit NF-kB essential modifier (NEMO), results in phosphorylation, ubiquitination and degradation of IkBa, exposing the NLS of NF-kB, leading to its nuclear accumulation.…”

Section: Introductionmentioning

confidence: 99%

Signals from within: the DNA-damage-induced NF-κB response

2006

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An appropriate response to genotoxic stress is essential for maintenance of genome stability and avoiding the passage to neoplasia. Nuclear factor jB (NF-jB) is activated as part of the DNA damage response and is thought to orchestrate a cell survival pathway, which, together with the activation of cell cycle checkpoints and DNA repair, allows the cell in cases of limited damage to restore a normal life cycle, unharmed. In this respect, NF-jB is one of the main factors accounting for chemotherapy resistance and as such impedes effective cancer treatment, representing an important drug target. Despite this high clinical relevance, signalling cascades leading to DNA damageinduced NF-jB activation are poorly understood and the use of highly divergent experimental set-ups in the past led to many controversies in the field. Therefore, in this review, we will try to summarize the current knowledge of distinct DNA damage-induced NF-jB signalling pathways. Cell Death and Differentiation (2006) Keywords: NF-kB; DNA damage; signalling Abbreviations: ATM, ataxia telangiectasia mutated; ATR, ATM-related kinase; BAFF, B-cell-activating factor of the TNF family; CK2, casein kinase 2; CPT, camptothecin; DD, death domain; DNA-PK, DNA-protein kinase; DSB, double-strand break; HDAC, histone deacetylase; HED-ID, hypohydrotic ectodermal dysplasia with severe immunodeficiency; FAT, Frap, ATM and Trapp; IkB, inhibitor of kB; IKK, IkB kinase; IR, g-irradiation; LRR, leucine-rich repeat; LT, lymphotoxin; NEMO, NF-kB essential modifier; NF-kB, nuclear factor kB; NIK, NF-kBinducing kinase; NLS, nuclear localization signal; PI3K, phosphoinositide 3-kinase; PKC, protein kinase C; RHD, Rel homology domain; RSK1, ribosomal S6 kinase 1; TAD, transcriptional activation domain; TNF, tumour necrosis factor; UV, ultraviolet Canonical, Alternative and Atypical Pathways: The Roads to NF-jB Active nuclear factor kB (NF-kB) transcription factors are composed of dimeric combinations of members of the Rel transcription factor family (for reviews, see Rothwarf and Karin 1 and Hayden and Ghosh 2 ). In mammals, five different Rel family members have been identified: RelA (p65), RelB, c-Rel, NF-kB1 (p50 and its precursor p105) and NF-kB2 (p52 and its precursor p100), which can form hetero-or homodimers. Heterodimers of RelA/p65 and p50 are the most abundant in most cells, and the term NF-kB is often used to refer to this complex. All Rel family members are characterized by the presence of a 300-amino-acid long N-terminal stretch, called the Rel homology domain (RHD), which is responsible for DNA binding, dimerization and interaction with inhibitor of kB (IkB) proteins. Interaction with IkB masks the nuclear localization signal (NLS) present in the RHD and sequesters NF-kB in an inactive form in the cytoplasm. In addition, RelA/p65, RelB and c-Rel also possess a transcriptional activation domain (TAD), rendering NF-kB a potent transcription factor. p50 and p52 do not have similar domains and therefore homodimers of these proteins can repress trans...

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“…Upon stimulation by LPS, the TLR4/MD2 complex relays signals that effectuate phosphorylation and ubiquitin-mediated degradation of I-jBa (reviewed in [11]), allowing for phosphorylation of p65 and entry of p65/p50 heterodimers into the nucleus, where they bind to cognate target gene promoters (reviewed in [11][12][13]). …”

Section: Introductionmentioning

confidence: 99%

The zinc finger protein Gfi1 acts upstream of TNF to attenuate endotoxin‐mediated inflammatory responses in the lung

et al. 2006

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Gfi1 is a 55-kD nuclear zinc finger protein that is differentially expressed in lymphoid and myeloid cells. Gfi1 -/-mice show a very strong systemic response to the endotoxin LPS and die rapidly within 36 h with symptoms of septic shock. Here we report that the pathohysiological processes for this exaggerated inflammatory response take place in the lung. After LPS treatment, lungs of Gfi1 -/-mice showed a rapid accumulation of mononuclear cells and a significant overproduction of inflammatory cytokines such as TNF, IL-1b and IL-6. Increased cytokine production was also observed in blood-free perfused lungs from Gfi1 -/-mice exposed to either LPS or overventilation. Alveolar macrophages but not airway epithelial cells from Gfi1 -/-mice were found to be responsible for the enhanced cytokine production. Strikingly, when the TNF gene was deleted, Gfi1 -/-animals were completely rescued from LPS hypersensitivity and had significantly lower IL-1b and IL-6 levels. We conclude that the unrestrained endotoxin response of Gfi1 -/-mice occurs mainly in the lung and that Gfi1 represents a novel factor limiting the inflammatory immune response of this organ, and propose that Gfi1 exerts its regulatory function in alveolar macrophages downstream of the LPS receptor (TLR4) and upstream of TNF.

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IκB kinases: key regulators of the NF-κB pathway

Cited by 599 publications

References 71 publications

Resveratrol‐induced apoptosis in MCF‐7 human breast cancer cells involves a caspase‐independent mechanism with downregulation of Bcl‐2 and NF‐κB

Resveratrol‐induced apoptosis in MCF‐7 human breast cancer cells involves a caspase‐independent mechanism with downregulation of Bcl‐2 and NF‐κB

Signals from within: the DNA-damage-induced NF-κB response

The zinc finger protein Gfi1 acts upstream of TNF to attenuate endotoxin‐mediated inflammatory responses in the lung

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