Faculty Opinions recommendation of Nuclear factor-kappaB (NF-kappaB) regulates proliferation and branching in mouse mammary epithelium.

Recently isolated trophoblasts express nitric oxide synthase 2 (NOS-2) and cyclooxygenase 2 (COX-2), decreasing the levels of the corresponding mRNAs when the cells were maintained in culture. The sustained expression of COX-2 and NOS-2 in trophoblasts was dependent on the activation of nuclear factor kappaB (NF-kappaB) since proteasome inhibitors and antioxidants that abrogated NF-kappaB activity suppressed the induction of both genes. The time-dependent fall of the mRNA levels of NOS-2 and COX-2 paralleled the inhibition of NF-kappaB, determined by electrophoretic mobility shift assays, and the increase of the IkappaBalpha and IkappaBbeta inhibitory proteins. Isolated trophoblasts synthesized reactive oxygen intermediates (ROI), a process impaired after culturing the cells, and that might be involved in the NF-kappaB activation process. Moreover, treatment of recently isolated cells with ROI scavengers suppressed the expression of COX-2 and NOS-2. Challenge of trophoblasts with interleukin-1beta up-regulated the expression of both proteins, an effect that was potentiated by lipopolysaccharide. These results indicate that the physiological expression of NOS-2 and COX-2 in trophoblasts involves a sustained activation of NF-kappaB which inhibition abrogates the inducibility of both genes.

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Induction of nuclear factor kappaB by the CD30 receptor is mediated by TRAF1 and TRAF2.

Molecular and Cellular Biology ◽

10.1128/mcb.17.3.1535 ◽

1997 ◽

Vol 17 (3) ◽

pp. 1535-1542 ◽

Cited By ~ 161

Author(s):

C S Duckett ◽

R W Gedrich ◽

M C Gilfillan ◽

C B Thompson

Keyword(s):

Amino Acid ◽

Tumor Necrosis Factor Receptor ◽

Proximal Region ◽

Dominant Negative ◽

Nuclear Factor Kappab ◽

Nuclear Factor ◽

Protein Levels ◽

Surface Receptor ◽

Nf Kappab ◽

Carboxy Terminal

CD30 is a lymphoid cell-specific surface receptor which was originally identified as an antigen expressed on Hodgkin's lymphoma cells. Activation of CD30 induces the nuclear factor kappaB (NF-kappaB) transcription factor. In this study, we define the domains in CD30 which are required for NF-kappaB activation. Two separate elements of the cytoplasmic domain which were capable of inducing NF-kappaB independently of one another were identified. The first domain (domain 1) mapped to a approximately 120-amino-acid sequence in the membrane-proximal region of the CD30 cytoplasmic tail, between residues 410 and 531. A second, more carboxy-terminal region (domain 2) was identified between residues 553 and 595. Domain 2 contains two 5- to 10-amino-acid elements which can mediate the binding of CD30 to members of the tumor necrosis factor receptor-associated factor (TRAF) family of signal transducing proteins. Coexpression of CD30 with TRAF1 or TRAF2 but not TRAF3 augmented NF-kappaB activation through domain 2 but not domain 1. NF-kappaB induction through domain 2 was inhibited by coexpression of either full-length TRAF3 or dominant negative forms of TRAF1 or TRAF2. In contrast, NF-kappaB induction by domain 1 was not affected by alterations in TRAF protein levels. Together, these data support a model in which CD30 can induce NF-kappaB by both TRAF-dependent and -independent mechanisms. TRAF-dependent induction of NF-kappaB appears to be regulated by the relative levels of individual TRAF proteins in the cell.

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Negative regulation of nuclear factor-kappaB activation and function by glucocorticoids

Journal of Molecular Endocrinology ◽

10.1677/jme.0.0280069 ◽

2002 ◽

Vol 28 (2) ◽

pp. 69-78 ◽

Cited By ~ 157

Author(s):

WY Almawi ◽

OK Melemedjian

Keyword(s):

Transcription Factors ◽

Transcriptional Activation ◽

Promoter Region ◽

Nuclear Translocation ◽

Nuclear Factor Kappab ◽

Nuclear Factor ◽

Creb Binding Protein ◽

Transcriptional Initiation ◽

Nf Kappab ◽

And Function

Glucocorticoids (GCs) exert their anti-inflammatory and antiproliferative effects principally by inhibiting the expression of cytokines and adhesion molecules. Mechanistically, GCs diffuse through the cell membrane, and bind to their inactive cytosolic receptors (GRs), which then undergo conformational modifications that allow for their nuclear translocation. In the nucleus, activated GRs modulate transcriptional events by directly associating with DNA elements, compatible with the GCs response elements (GRE) motif, and located in variable copy numbers and at variable distances from the TATA box, in the promoter region of GC-responsive genes. In addition, activated GRs also acted by antagonizing the activity of transcription factors, in particular nuclear factor-kappaB (NF-kappaB), by direct and indirect mechanisms. GCs induced gene transcription and protein synthesis of the NF-kappaB inhibitor, IkappaB. Activated GR also antagonized NF-kappaB activity through protein-protein interaction involving direct complexing with, and inhibition of, NF-kappaB binding to DNA (Simple Model), or association with NF-kappaB bound to the kappaB DNA site (Composite Model). In addition, and according to the Transmodulation Model, GRE-bound GR may interact with and inhibit the activity of kappaB-bound NF-kappaB via a mechanism involving cross-talk between the two transcription factors. Lastly, GR may compete with NF-kappaB for nuclear coactivators, including CREB binding protein and p300, thereby reducing and inhibiting transcriptional activation by NF-kappaB. It should be noted that, in exerting its effect, activated GR did not affect the correct assembly of the pre-initiation (DAB) complex, but acted rather more proximally in inhibiting the correct assembly of transcription factors in the promoter region, and thus transcriptional initiation.

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Regulation of nuclear factor kappaB by corticosteroids in rat mesangial cells.

Journal of the American Society of Nephrology ◽

10.1681/asn.v991620 ◽

1998 ◽

Vol 9 (9) ◽

pp. 1620-1628

Author(s):

R B Auwardt ◽

S J Mudge ◽

C G Chen ◽

D A Power

Keyword(s):

Mesangial Cells ◽

Kidney Diseases ◽

Binding Activity ◽

Proliferative Glomerulonephritis ◽

Nuclear Factor Kappab ◽

Nuclear Factor ◽

Glomerular Mesangial Cells ◽

Mesangial Proliferative Glomerulonephritis ◽

Interleukin 1Beta ◽

Nf Kappab

Nuclear factor kappaB (NF-kappaB) is one of the most important proinflammatory transcription factors. The anti-inflammatory activity of steroids in leukocytes is partly due to inhibition of signaling by NF-kappaB, but it is not known whether steroids inhibit NF-kappaB in kidney cells. Since the mesangial cell is important in several kidney diseases, especially mesangial proliferative glomerulonephritis, the aims of this study were: (1) to define the mechanism of NF-kappaB activation in rat glomerular mesangial cells; and (2) to determine whether steroids inhibit activation of NF-kappaB in these cells. Electrophoretic mobility shift assays (EMSA) showed that interleukin-1beta and tumor necrosis factor-alpha activated NF-kappaB from 15 min to 48 h after stimulation. Supershift EMSA demonstrated that p65 and p50 were the predominant subunits involved. Degradation of the inhibitory subunit IkappaB-alpha was first observed 15 min after stimulation by Western blot, was maximal at 15 to 30 min (>90% by densitometry), and had returned to near normal levels at 90 min. In contrast, IkappaB-beta was maximally degraded at 60 to 120 min and was still reduced at 48 h (<50% of the untreated level). Although treatment of mesangial cells with dexamethasone increased IkappaB-alpha mRNA by 1.92x and protein by 1.45x over controls, pretreatment did not inhibit degradation of IkappaB-alpha or -beta in response to stimulation, or prevent the increase in NF-kappaB binding activity shown by EMSA. However, dexamethasone significantly inhibited the increase in monocyte chemoattractant protein-1 mRNA seen after stimulation with interleukin 1beta, although this was not complete. It did not reduce transcription of an NF-kappaB reporter. In comparison, the pyrrolidine derivative of dithiocarnamate (PDTC), a known inhibitor of NF-kappaB, prevented the increase in NF-kappaB binding activity and significantly reduced transcription of the NF-kappaB reporter. These studies suggest that steroids can partially inhibit transcriptional activation by NF-kappaB in mesangial cells but not through an increase in IkappaB-alpha protein alone. Their effect must occur at the promoter and may be restricted to some NF-kappaB-responsive genes. Therapies that block NF-kappaB more effectively than steroids in mesangial cells, therefore, may be useful in the treatment of mesangial proliferative glomerulonephritis.

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The nuclear factor-kappaB (NF-kappaB): from a versatile transcription factor to a ubiquitous therapeutic target.

Acta Biochimica Polonica ◽

10.18388/abp.2006_3293 ◽

2006 ◽

Vol 53 (4) ◽

pp. 651-662 ◽

Cited By ~ 21

Author(s):

Laura L Yates ◽

Dariusz C Górecki

Keyword(s):

Nuclear Factor Kappab ◽

Specific Response ◽

Nuclear Factor ◽

Therapeutic Approaches ◽

Altered Regulation ◽

Nf Kappab ◽

Novel Therapeutic Strategies ◽

And Function

The nuclear factor-kappaB (NF-kappaB) transcription factors regulate a plethora of cellular pathways and processes including the immune response, inflammation, proliferation, apoptosis and calcium homeostasis. In addition to the complexity of its physiological roles, the composition and function of this family of proteins is very complicated. While the basic understanding of NF-kappaB signalling is extensive, relatively little is know of the in vivo dynamics of this pathway or what controls the balance between various outcomes. Although we know a large number of NF-kappaB-responsive genes, the contribution of these genes to a specific response is not always clear. Finally, the involvement of NF-kappaB in pathological processes is only now beginning to be unravelled. In addition to cancer and immunodeficiency disorders, altered regulation of NF-kappaB has been associated with several inherited diseases. These findings indicate that modulation of the NF-kappaB pathways may be beneficial. However, our limited knowledge of NF-kappaB signalling hinders therapeutic approaches: in many situations it is not clear whether the enhancement or inhibition of NF-kappaB activity would be beneficial or which pathways to interfere with and what the required level of activation is. Further studies of the role of NF-kappaB are needed as these may result in novel therapeutic strategies for a wide variety of diseases.

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Effect of dexamethasone on interleukin-1beta-(IL-1beta)-induced nuclear factor-kappaB (NF-kappaB) and kappaB-dependent transcription in epithelial cells

European Journal of Biochemistry ◽

10.1046/j.1432-1327.1998.2540081.x ◽

1998 ◽

Vol 254 (1) ◽

pp. 81-89 ◽

Cited By ~ 72

Author(s):

Robert Newton ◽

Lorraine A. Hart ◽

David A. Stevens ◽

Martin Bergmann ◽

Louise E. Donnelly ◽

...

Keyword(s):

Epithelial Cells ◽

Nuclear Factor Kappab ◽

Nuclear Factor ◽

Interleukin 1Beta ◽

Nf Kappab

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Nuclear Factor-κB (NF-κB) Regulates Proliferation and Branching in Mouse Mammary Epithelium

Molecular Biology of the Cell ◽

10.1091/mbc.12.5.1445 ◽

2001 ◽

Vol 12 (5) ◽

pp. 1445-1455 ◽

Cited By ~ 101

Author(s):

Dana M. Brantley ◽

Chih-Li Chen ◽

Rebecca S. Muraoka ◽

Paul B. Bushdid ◽

Jonathan L. Bradberry ◽

...

Keyword(s):

Epithelial Cell ◽

Mammary Epithelium ◽

Nuclear Factor Κb ◽

Cell Number ◽

Breast Cancer Cell Lines ◽

Mammary Tissue ◽

Nuclear Factor ◽

Aberrant Expression ◽

Mouse Mammary Epithelium

The nuclear factor-κB (NF-κB) family of transcription factors has been shown to regulate proliferation in several cell types. Although recent studies have demonstrated aberrant expression or activity of NF-κB in human breast cancer cell lines and tumors, little is known regarding the precise role of NF-κB in normal proliferation and development of the mammary epithelium. We investigated the function of NF-κB during murine early postnatal mammary gland development by observing the consequences of increased NF-κB activity in mouse mammary epithelium lacking the gene encoding IκBα, a major inhibitor of NF-κB. Mammary tissue containing epithelium from inhibitor κBα (IκBα)-deficient female donors was transplanted into the gland-free mammary stroma of wild-type mice, resulting in an increase in lateral ductal branching and pervasive intraductal hyperplasia. A two- to threefold increase in epithelial cell number was observed in IκBα-deficient epithelium compared with controls. Epithelial cell proliferation was strikingly increased in IκBα-deficient epithelium, and no alteration in apoptosis was detected. The extracellular matrix adjacent to IκBα-deficient epithelium was reduced. Consistent with in vivo data, a fourfold increase in epithelial branching was also observed in purified IκBα-deficient primary epithelial cells in three-dimensional culture. These data demonstrate that NF-κB positively regulates mammary epithelial proliferation, branching, and functions in maintenance of normal epithelial architecture during early postnatal development.

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The role of nuclear factor-kappaB in the development of autoimmune diseases: a link between genes and environment.

Acta Biochimica Polonica ◽

10.18388/abp.2008_3023 ◽

2008 ◽

Vol 55 (4) ◽

pp. 629-647 ◽

Cited By ~ 28

Author(s):

Alina Kuryłowicz ◽

Janusz Nauman

Keyword(s):

Autoimmune Diseases ◽

Lupus Erythematosus ◽

Therapeutic Potential ◽

Nuclear Factor Kappab ◽

Nuclear Factor ◽

Failure Initiation ◽

Self Tolerance ◽

Genes And Environment ◽

Bowel Diseases ◽

Nf Kappab

Although autoimmune diseases are relatively common, mechanisms that lead to their development remain largely unknown. Nuclear factor-kappaB (NF-kappaB), as a key transcription factor involved in the regulation of immune responses and apoptosis, appears to be a good candidate for studies on the pathogenesis of autoimmunity. This review presents how perturbations of the NF-kappaB signaling pathway may contribute to self-tolerance failure, initiation of autoimmune inflammatory response as well as its persistent maintenance and therefore to the development of common autoimmune diseases including rheumatoid arthritis, multiple sclerosis, type 1 diabetes mellitus, thyroid autoimmune diseases, systemic lupus erythematosus as well as inflammatory bowel diseases and psoriasis. A special emphasis is put on the genetic variations in the NF-kappaB related genes and their possible association with susceptibility to autoimmune diseases, as well as on the therapeutic potential of the NF-kappaB targeted strategies in the treatment of autoimmunity.

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