Series Introduction: The transcription factor NF-κB and human disease

doi:10.1172/JCI11891

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Series Introduction: The transcription factor NF-κB and human disease

Journal Article•DOI•

Series Introduction: The transcription factor NF-κB and human disease

Albert S. Baldwin¹•Institutions (1)

University of North Carolina at Chapel Hill¹

01 Jan 2001-Journal of Clinical Investigation (American Society for Clinical Investigation)-Vol. 107, Iss: 1, pp 3-6

TL;DR: It is shown that the transcription factor NF-κB has been shown to be the target of several anti-inflammatory and anticancer drugs.

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Abstract: Beginning with its discovery in 1986 and continuing through the present, the transcription factor NF-κB has attracted widespread interest based on its unusual regulation, the variety of stimuli that activate it, the diverse genes and biological responses that it controls, the striking evolutionary conservation of structure and function among family members, and its apparent involvement in a variety of human diseases (Table (Table1).1). Importantly, and consistent with the last point, NF-κB has been shown to be the target of several anti-inflammatory and anticancer drugs.

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Journal Article•DOI•

Missing Pieces in the NF-κB Puzzle

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Sankar Ghosh¹, Michael Karin²•Institutions (2)

Yale University¹, University of California, San Diego²

19 Apr 2002-Cell

TL;DR: In this paper, a review of recent progress as well as unanswered questions regarding the regulation and function of NF-kappaB and IKK is presented, focusing on recent progress and unanswered questions.

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3,342 citations

Journal Article•DOI•

Oxidative Stress and Stress-Activated Signaling Pathways: A Unifying Hypothesis of Type 2 Diabetes

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Joseph L. Evans, Ira D. Goldfine¹, Betty A. Maddux¹, Gerold M. Grodsky¹•Institutions (1)

University of California, San Francisco¹

01 Oct 2002-Endocrine Reviews

TL;DR: A unifying hypothesis is proposed whereby hyperglycemia and FFA-induced activation of the nuclear factor-kappaB, p38 MAPK, and NH2-terminal Jun kinases/stress-activated protein kinases stress pathways plays a key role in causing late complications in type 1 and type 1 diabetes, along with insulin resistance and impaired insulin secretion in type 2 diabetes.

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Abstract: In both type 1 and type 2 diabetes, the late diabetic complications in nerve, vascular endothelium, and kidney arise from chronic elevations of glucose and possibly other metabolites including free fatty acids (FFA). Recent evidence suggests that common stress-activated signaling pathways such as nuclear factor-kappaB, p38 MAPK, and NH2-terminal Jun kinases/stress-activated protein kinases underlie the development of these late diabetic complications. In addition, in type 2 diabetes, there is evidence that the activation of these same stress pathways by glucose and possibly FFA leads to both insulin resistance and impaired insulin secretion. Thus, we propose a unifying hypothesis whereby hyperglycemia and FFA-induced activation of the nuclear factor-kappaB, p38 MAPK, and NH2-terminal Jun kinases/stress-activated protein kinases stress pathways, along with the activation of the advanced glycosylation end-products/receptor for advanced glycosylation end-products, protein kinase C, and sorbitol stress pathways, plays a key role in causing late complications in type 1 and type 2 diabetes, along with insulin resistance and impaired insulin secretion in type 2 diabetes. Studies with antioxidants such as vitamin E, alpha-lipoic acid, and N-acetylcysteine suggest that new strategies may become available to treat these conditions.

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2,090 citations

Journal Article•DOI•

International Union of Pharmacology. XLV. Classification of the Kinin Receptor Family: from Molecular Mechanisms to Pathophysiological Consequences

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L. M. Fredrik Leeb-Lundberg¹, François Marceau, Werner Müller-Esterl, Douglas J. Pettibone, Bruce L. Zuraw - Show less +1 more•Institutions (1)

Lund University¹

01 Mar 2005-Pharmacological Reviews

TL;DR: This review is a comprehensive presentation of the current understanding of B1 and B2 receptors in terms of molecular and cell biology, physiology, pharmacology, and involvement in human disease and drug development.

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Abstract: Kinins are proinflammatory peptides that mediate numerous vascular and pain responses to tissue injury. Two pharmacologically distinct kinin receptor subtypes have been identified and characterized for these peptides, which are named B1 and B2 and belong to the rhodopsin family of G protein-coupled receptors. The B2 receptor mediates the action of bradykinin (BK) and lysyl-bradykinin (Lys-BK), the first set of bioactive kinins formed in response to injury from kininogen precursors through the actions of plasma and tissue kallikreins, whereas the B(1) receptor mediates the action of des-Arg9-BK and Lys-des-Arg9-BK, the second set of bioactive kinins formed through the actions of carboxypeptidases on BK and Lys-BK, respectively. The B2 receptor is ubiquitous and constitutively expressed, whereas the B1 receptor is expressed at a very low level in healthy tissues but induced following injury by various proinflammatory cytokines such as interleukin-1beta. Both receptors act through G alpha(q) to stimulate phospholipase C beta followed by phosphoinositide hydrolysis and intracellular free Ca2+ mobilization and through G alpha(i) to inhibit adenylate cyclase and stimulate the mitogen-activated protein kinase pathways. The use of mice lacking each receptor gene and various specific peptidic and nonpeptidic antagonists have implicated both B1 and B2 receptors as potential therapeutic targets in several pathophysiological events related to inflammation such as pain, sepsis, allergic asthma, rhinitis, and edema, as well as diabetes and cancer. This review is a comprehensive presentation of our current understanding of these receptors in terms of molecular and cell biology, physiology, pharmacology, and involvement in human disease and drug development.

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933 citations

Cites background from "Series Introduction: The transcript..."

...In animal models, noxious treatments applied in vivo render subsequently isolated smooth muscle preparations immediately responsive to B1 receptor agonists (e.g., the chemical inflammation of the rat urinary bladder, the injection of a sublethal dose of LPS in the rabbit; Marceau et al., 1998)....
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...NF- B is a transcription factor (or more precisely, a family of factors) controlling the expression of numerous genes associated with immunity and inflammation under the effect of receptors for inflammatory cytokines and LPS (Baldwin, 2001)....
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...Radioligand-based techniques applied to cultured rabbit vascular smooth muscle cells essentially showed that cytokines such as IL-1, EGF, and tumor necrosis factor- , but also fetal bovine serum and LPS, up-regulate B1 receptor abundance (Bmax) without changing the affinity (KD) of the radioligand (Schneck et al., 1994; Galizzi et al., 1994; Haddad et al., 2000; Sabourin et al., 2002b) and confirmed the inhibitory effect of glucocorticoids....
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...Other evidence suggests that a second genomic site downstream from the 5 promoter may be involved in LPS and Lys-des-Arg-BK inducible promoter activity....
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...Transfection of a B1 receptor minigene (containing a 1.8-kb promoter, exon 1, 1.5 kb of intron 1, exon 2, intron 2, and the luciferase gene) into IMR 90 cells resulted in promoter activity which was activated by LPS and Lysdes-Arg-BK; however, transfection of the 1.8-kb promoter fused to the luciferase gene did not show increased promoter activity in response to LPS or Lys-desArg-BK (Yang et al., 2001a)....
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Journal Article•DOI•

The Interplay between the Glucocorticoid Receptor and Nuclear Factor-κB or Activator Protein-1: Molecular Mechanisms for Gene Repression

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Karolien De Bosscher¹, Wim Vanden Berghe¹, Guy Haegeman¹•Institutions (1)

Ghent University¹

01 Aug 2003-Endocrine Reviews

TL;DR: The cellular signaling pathways identified as important regulators of inflammation are the signal transduction cascades mediated by the nuclear factor-kappaB and the activator protein-1, which can both be modulated by glucocorticoids.

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Abstract: The inflammatory response is a highly regulated physiological process that is critically important for homeostasis. A precise physiological control of inflammation allows a timely reaction to invading pathogens or to other insults without causing overreaction liable to damage the host. The cellular signaling pathways identified as important regulators of inflammation are the signal transduction cascades mediated by the nuclear factor-kappaB and the activator protein-1, which can both be modulated by glucocorticoids. Their use in the clinic includes treatment of rheumatoid arthritis, asthma, allograft rejection, and allergic skin diseases. Although glucocorticoids have been widely used since the late 1940s, the molecular mechanisms responsible for their antiinflammatory activity are still under investigation. The various molecular pathways proposed so far are discussed in more detail.

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884 citations

Journal Article•DOI•

Prolonged Exposure to Free Fatty Acids Has Cytostatic and Pro-Apoptotic Effects on Human Pancreatic Islets: Evidence that β-Cell Death Is Caspase Mediated, Partially Dependent on Ceramide Pathway, and Bcl-2 Regulated

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Roberto Lupi¹, Francesco Dotta, Lorella Marselli, Silvia Del Guerra, Matilde Masini, Carmela Santangelo, G Patanè, Ugo Boggi, Salvatore Piro, M. Anello, Ettore Bergamini, Franco Mosca, Umberto Di Mario, Stefano Del Prato, Piero Marchetti - Show less +11 more•Institutions (1)

University of Pisa¹

01 May 2002-Diabetes

TL;DR: Extended exposure to FFAs has cytostatic and pro-apoptotic effects on human pancreatic beta-cells, likely to be due to the FFA-induced reduction of intraislet glucose metabolism, and the proapoptosis effects are mostly caspase mediated, partially dependent on ceramide pathway, and possibly Bcl-2 regulated.

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Abstract: In an effort to better understand the phenomenon of lipotoxicity in human β-cells, we evaluated the effects of 48-h preculture with 1.0 or 2.0 mmol/l free fatty acid (FFA) (2:1 oleate to palmitate) on the function and survival of isolated human islets and investigated some of the possible mechanisms. Compared with control islets, triglyceride content was significantly increased and insulin content and glucose-stimulated insulin release were significantly reduced in islets precultured with increased FFA concentrations. These changes were accompanied by a significant reduction of glucose utilization and oxidation. By cell death detection techniques, it was observed that exposure to FFAs induced a significant increase of the amount of dead cells. Electron microscopy showed the involvement of β-cells, with morphological appearance compatible with the presence of apoptotic phenomena. FFA-induced islet cell death was blocked by inhibition of upstream caspases and partially prevented by inhibiton of ceramide synthesis or serine protease activity, whereas inhibition of nitric oxide synthesis had no effect. RT-PCR studies revealed no major change of iNOS and Bax mRNA expression and a marked decrease of Bcl-2 mRNA expression in the islets cultured with FFA. Thus, prolonged exposure to FFAs has cytostatic and pro-apoptotic effects on human pancreatic β-cells. The cytostatic action is likely to be due to the FFA-induced reduction of intraislet glucose metabolism, and the proapoptotic effects are mostly caspase mediated, partially dependent on ceramide pathway, and possibly Bcl-2 regulated.

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618 citations

Cites background from "Series Introduction: The transcript..."

...If so, ceramide activation of NF B (27) would cause upregulation of gene(s) other than the iNOS gene, which would not be surprising considering the pleiotropic effects of NF B on gene regulation (28)....
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Journal Article•DOI•

THE NF-κB AND IκB PROTEINS: New Discoveries and Insights

[...]

Albert S. Baldwin¹•Institutions (1)

University of North Carolina at Chapel Hill¹

01 Jan 1996-Annual Review of Immunology

TL;DR: The transcription factor NF-κB has attracted widespread attention among researchers in many fields based on its unusual and rapid regulation, the wide range of genes that it controls, its central role in immunological processes, the complexity of its subunits, and its apparent involvement in several diseases.

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Abstract: ▪ Abstract The transcription factor NF-κB has attracted widespread attention among researchers in many fields based on the following: its unusual and rapid regulation, the wide range of genes that it controls, its central role in immunological processes, the complexity of its subunits, and its apparent involvement in several diseases. A primary level of control for NF-κB is through interactions with an inhibitor protein called IκB. Recent evidence confirms the existence of multiple forms of IκB that appear to regulate NF-κB by distinct mechanisms. NF-κB can be activated by exposure of cells to LPS or inflammatory cytokines such as TNF or IL-1, viral infection or expression of certain viral gene products, UV irradiation, B or T cell activation, and by other physiological and nonphysiological stimuli. Activation of NF-κB to move into the nucleus is controlled by the targeted phosphorylation and subsequent degradation of IκB. Exciting new research has elaborated several important and unexpected findings that...

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5,833 citations

"Series Introduction: The transcript..." refers background in this paper

...The cloning of the first form of IκBα was facilitated by the observed homology between it and the COOHterminal region of the p105 of NF-κB (2)....
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...The activation of NF-κB is normally associated with induction of phosphorylation of IκB, followed by its degradation by the proteasome and nuclear translocation (2, 3)....
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...Drosophila has an IκB homologue known as Cactus, whose interactions with Dorsal are under control of Toll, a homologue of the IL-1 receptor (2, 3)....
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...An interesting member of the IκB family is Bcl-3, which functions through interactions with certain NF-κB subunits to promote transcription (2, 3)....
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...Genes regulated by NF-κB include those encoding IL-2, IL-6, IL-8, the IL-2 receptor, the IL-12 p40 subunit, VCAM-1, ICAM-1, TNF-α, IFN-γ, and c-Myc (2, 3)....
[...]

Journal Article•DOI•

NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses

[...]

Sankar Ghosh¹, Michael J. May, Elizabeth Kopp•Institutions (1)

Yale University¹

01 Jan 1998-Annual Review of Immunology

TL;DR: Recently, significant advances have been made in elucidating the details of the pathways through which signals are transmitted to the NF-kappa B:I kappa B complex in the cytosol and their implications for the study of NF-Kappa B.

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Abstract: ▪ Abstract The transcription factor NF-κB, more than a decade after its discovery, remains an exciting and active area of study. The involvement of NF-κB in the expression of numerous cytokines and adhesion molecules has supported its role as an evolutionarily conserved coordinating element in the organism's response to situations of infection, stress, and injury. Recently, significant advances have been made in elucidating the details of the pathways through which signals are transmitted to the NF-κB:IκB complex in the cytosol. The field now awaits the discovery and characterization of the kinase responsible for the inducible phosphorylation of IκB proteins. Another exciting development has been the demonstration that in certain situations NF-κB acts as an anti-apoptotic protein; therefore, elucidation of the mechanism by which NF-κB protects against cell death is an important goal. Finally, the generation of knockouts of members of the NF-κB/IκB family has allowed the study of the roles of these protein...

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5,324 citations

"Series Introduction: The transcript..." refers background in this paper

...Other forms of IκB have been identified, including IκBβ and IκBε (3)....
[...]
...The activation of NF-κB is normally associated with induction of phosphorylation of IκB, followed by its degradation by the proteasome and nuclear translocation (2, 3)....
[...]
...Drosophila has an IκB homologue known as Cactus, whose interactions with Dorsal are under control of Toll, a homologue of the IL-1 receptor (2, 3)....
[...]
...An interesting member of the IκB family is Bcl-3, which functions through interactions with certain NF-κB subunits to promote transcription (2, 3)....
[...]
...Genes regulated by NF-κB include those encoding IL-2, IL-6, IL-8, the IL-2 receptor, the IL-12 p40 subunit, VCAM-1, ICAM-1, TNF-α, IFN-γ, and c-Myc (2, 3)....
[...]

Journal Article•DOI•

Phosphorylation meets ubiquitination: the control of NF-[kappa]B activity.

[...]

Michael Karin¹, Yinon Ben-Neriah•Institutions (1)

University of California, San Diego¹

01 Jan 2000-Annual Review of Immunology

TL;DR: Recent progress has been made in understanding the details of the signaling pathways that regulate NF-kappaB activity, particularly those responding to the proinflammatory cytokines tumor necrosis factor-alpha and interleukin-1.

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Abstract: NF-κB (nuclear factor-κB) is a collective name for inducible dimeric transcription factors composed of members of the Rel family of DNA-binding proteins that recognize a common sequence motif. NF-κ...

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4,724 citations

Journal Article•DOI•

Nuclear factor-kappaB: a pivotal transcription factor in chronic inflammatory diseases.

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Peter J. Barnes¹, Michael Karin•Institutions (1)

National Institutes of Health¹

10 Apr 1997-The New England Journal of Medicine

TL;DR: In chronic inflammatory diseases, such as asthma, rheumatoid arthritis, inflammatory bowel disease, and psoriasis, several cytokines recruit activated immune and inflammatory cells to the site of lesions, thereby amplifying and perpetuating the inflammatory state.

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Abstract: In chronic inflammatory diseases, such as asthma, rheumatoid arthritis, inflammatory bowel disease, and psoriasis, several cytokines recruit activated immune and inflammatory cells to the site of lesions, thereby amplifying and perpetuating the inflammatory state.1 These activated cells produce many other mediators of inflammation. What causes these diseases is still a mystery, but the disease process results from an interplay of genetic and environmental factors. Genes, such as those for atopy in asthma and for HLA antigens in rheumatoid arthritis and inflammatory bowel disease, may determine a patient's susceptibility to the disease and the disease's severity, but environmental factors, often unknown, . . .

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4,624 citations

"Series Introduction: The transcript..." refers background in this paper

...Glucocorticoids such as prednisone have been shown to block NF-κB activation by different mechanisms in different cell types (11, 17)....
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...Thus, the ability of NF-κB to activate transcription of genes encoding cell adhesion molecules (ICAM-1, VCAM-1, E-selectin) and chemoattractant proteins (monocyte chemoattractant protein-1 [MCP-1]) would lead to the recruitment of inflammatory cells to the lung, a hallmark of asthma (11)....
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Journal Article•DOI•

TNF- and Cancer Therapy-Induced Apoptosis: Potentiation by Inhibition of NF-κB

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Cun-Yu Wang¹, Marty W. Mayo¹, Albert S. Baldwin¹•Institutions (1)

University of North Carolina at Chapel Hill¹

01 Nov 1996-Science

TL;DR: The activation of the transcription factor nuclear factor-kappa B by tumor necrosis factor, ionizing radiation, or daunorubicin, was found to protect from cell killing, providing a mechanism of cellular resistance to killing by some apoptotic reagents.

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Abstract: Many cells are resistant to stimuli that can induce apoptosis, but the mechanisms involved are not fully understood. The activation of the transcription factor nuclear factor-kappa B (NF-kappaB) by tumor necrosis factor (TNF), ionizing radiation, or daunorubicin (a cancer chemotherapeutic compound), was found to protect from cell killing. Inhibition of NF-kappaB nuclear translocation enhanced apoptotic killing by these reagents but not by apoptotic stimuli that do not activate NF-kappaB. These results provide a mechanism of cellular resistance to killing by some apoptotic reagents, offer insight into a new role for NF-kappaB, and have potential for improvement of the efficacy of cancer therapies.

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2,637 citations