NF-κB Activation: The IκB Kinase Revealed?

Stancovski, Ilana; Baltimore, David

doi:10.1016/s0092-8674(00)80413-4

Cited by 476 publications

(280 citation statements)

References 18 publications

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“…To date, two IkB kinases have been identified, termed IKKa and IKKb . These two proteins have been shown to be activated by inducers of NF-kB, such as IL-1 and TNF, to phosphorylate S32 and S36 of IkB, and to play a key role in the activation of NF-kB by these cytokines (Mercurio et al, 1997;Stancovski and Baltimore, 1997;Bowie and O'Neill, 2000). The IKKs are part of a larger multiprotein complex called the IKK signalsome, which contains the IKK complex-associated protein (IKAP) and IKKg (also called NEMO), which is also crucial for NFkB activation (Cohen et al, 1998;Yamaoka et al, 1998;Bowie and O'Neill, 2000).…”

Section: Discussionmentioning

confidence: 99%

Upregulation of cyclooxygenase-2 is accompanied by increased expression of nuclear factor-κB and IκB kinase-α in human colorectal cancer epithelial cells

et al. 2003

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Cyclooxygenase-2 (COX-2) is selectively overexpressed in colorectal tumours. The mechanism of COX-2 induction is not fully understood, but requires de novo messenger RNA and protein synthesis, indicating regulation at the transcriptional level. Sequence analysis of the 5 0 -flanking region of the COX-2 gene shows two nuclear factor-kB (NF-kB) sites. Inhibition of this protein in model cell culture systems attenuates COX-2 expression and implies that NF-kB plays an important role in COX-2 induction. We measured COX-2, NF-kB and IkB kinase a (IKKa) protein expression in matched colonic biopsy samples comprising both nontumour and adjacent tumour tissue from 32 colorectal cancer patients using immunohistochemistry. There was none or very little expression of COX-2, NF-kB and IKKa in non-neoplastic colon epithelial cells, while the expression of all three of these proteins was significantly increased (Po0.05, Wilcoxon's signed rank test) in adjacent cancerous cells. Moreover, all three proteins were found to be coexpressed in the neoplastic epithelium, with the expression of COX-2 and NF-kB highly correlated (Pearson's correlation, Po0.005). There was no apparent correlation between enhanced COX-2, NF-kB or IKKa expression and tumour Dukes' stages. Our results are compatible with the hypothesis that IKKa and NF-kB are involved in COX-2 induction in these tumours and the lack of association between COX-2 expression and severity of disease as measured by Dukes' stage is consistent with the proposal that COX-2 expression is an early postinitiation event.

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Section: Discussionmentioning

confidence: 99%

Upregulation of cyclooxygenase-2 is accompanied by increased expression of nuclear factor-κB and IκB kinase-α in human colorectal cancer epithelial cells

et al. 2003

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“…In the present studies we found that HIV-tat induces serine phosphorylation of I B␣ in Jurkat cells but not in p56 lck -deficient cells, thus suggesting that p56 lck indirectly affects serine phosphorylation of I B␣. Thus p56 lck must modulate the function of I B␣ kinase I B kinase, which phosphorylates I B␣ (40).…”

Section: Discussionmentioning

confidence: 99%

Differential Requirement for p56lck in HIV-tat Versus TNF-Induced Cellular Responses: Effects on NF-κB, Activator Protein-1, c-Jun N-Terminal Kinase, and Apoptosis

Manna

Aggarwal

2000

The Journal of Immunology

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HIV-tat protein, like TNF, activates a wide variety of cellular responses, including NF-κB, AP-1, c-Jun N-terminal kinase (JNK), and apoptosis. Whether HIV-tat transduces these signals through the same mechanism as TNF is not known. In the present study we investigated the role of the T cell-specific tyrosine kinase p56lck in HIV-tat and TNF-mediated cellular responses by comparing the responses of Jurkat T cells with JCaM1 cells, an isogeneic lck-deficient T cell line. Treatment with HIV-tat protein activated NF-κB, degraded IκBα, and induced NF-κB-dependent reporter gene expression in a time-dependent manner in Jurkat cells but not in JCaM1 cells, suggesting the critical role of p56lck kinase. These effects were specific to HIV-tat, as activation of NF-κB by PMA, LPS, H2O2, and TNF was minimally affected. p56lck was also found to be required for HIV-tat-induced but not TNF-induced AP-1 activation. Similarly, HIV-tat activated the protein kinases JNK and mitogen-activated protein kinase kinase in Jurkat cells but not in JCaM1 cells. HIV-tat also induced cytotoxicity, activated caspases, and reactive oxygen intermediates in Jurkat cells, but not in JCaM1 cells. HIV-tat activated p56lck activity in Jurkat cells. Moreover, the reconstitution of JCaM1 cells with p56lck tyrosine kinase reversed the HIV-tat-induced NF-κB activation and cytotoxicity. Overall, our results demonstrate that p56lck plays a critical role in the activation of NF-κB, AP-1, JNK, and apoptosis by HIV-tat protein but has minimal or no role in activation of these responses by TNF.

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“…The most prevalent activated form of NF-κB is a heterodimer consisting of a p50 or p52 subunit and p65, which contains transactivation domains necessary for gene induction [74]. The genes regulated by NF-κB are diverse and include those involved in the inflammatory response, cell adhesion and growth control [75]. In resting cells, NF-κB dimers reside in the cytoplasm in an inactive form, associated to regulatory proteins called inhibitors of κB (IκB), of which the most important are IκBα, IκBβ, and IκBε.…”

Section: Activation Of the Nf-κb Systemmentioning

confidence: 99%

The immune system and cardiac repair

Frangogiannis

2008

Pharmacological Research

567

499

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Myocardial infarction is the most common cause of cardiac injury and results in acute loss of a large number of myocardial cells. Because the heart has negligible regenerative capacity, cardiomyocyte death triggers a reparative response that ultimately results in formation of a scar and is associated with dilative remodeling of the ventricle. Cardiac injury activates innate immune mechanisms initiating an inflammatory reaction. Toll Like Receptor-mediated pathways, the complement cascade and reactive oxygen generation induce Nuclear Factor (NF)-κB activation and upregulate chemokine and cytokine synthesis in the infarcted heart. Chemokines stimulate the chemotactic recruitment of inflammatory leukocytes into the infarct, while cytokines promote adhesive interactions between leukocytes and endothelial cells, resulting in transmigration of inflammatory cells into the site of injury. Monocyte subsets play distinct roles in phagocytosis of dead cardiomyocytes and in granulation tissue formation through the release of growth factors. Clearance of dead cells and matrix debris may be essential for resolution of inflammation and transition into the reparative phase. Transforming Growth Factor (TGF)-β plays a crucial role in cardiac repair by suppressing inflammation while promoting myofibroblast phenotypic modulation and extracellular matrix deposition. Myofibroblast proliferation and angiogenesis result in formation of highly vascularized granulation tissue. As the healing infarct matures, fibroblasts become apoptotic and a collagen-based matrix is formed, while many infarct neovessels acquire a muscular coat and uncoated vessels regress. Timely resolution of the inflammatory infiltrate and spatial containment of the inflammatory and reparative response into the infarcted area are essential for optimal infarct healing. Targeting inflammatory pathways following infarction may reduce cardiomyocyte injury and attenuate adverse remodeling. In addition, understanding the role of the immune system in cardiac repair is necessary in order to design optimal strategies for cardiac regeneration.

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NF-κB Activation: The IκB Kinase Revealed?

Cited by 476 publications

References 18 publications

Upregulation of cyclooxygenase-2 is accompanied by increased expression of nuclear factor-κB and IκB kinase-α in human colorectal cancer epithelial cells

Upregulation of cyclooxygenase-2 is accompanied by increased expression of nuclear factor-κB and IκB kinase-α in human colorectal cancer epithelial cells

Differential Requirement for p56lck in HIV-tat Versus TNF-Induced Cellular Responses: Effects on NF-κB, Activator Protein-1, c-Jun N-Terminal Kinase, and Apoptosis

The immune system and cardiac repair

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