The NF-κB regulatory network

Allan R. Brasier

Research output: Contribution to journalArticle

365 Citations (Scopus)

Abstract

Nuclear factor (NF)-κB is a family of seven structurally related transcription factors that play a central role in cardiovascular growth, stress response, and inflammation by controlling gene network expression. Although the NF- κB subunits are ubiquitously expressed, their actions are regulated in a celltype and stimulus-specific manner, allowing for a diverse spectrum of effects. For example, NF-κlB is activated by cytokines, reactive oxygen species, bacterial cell wall products, vasopressors, viral infection, and DNA damage. Recent molecular dissection of its mechanisms for activation has shown that NF-κlB can be induced by the so-called "canonical" and "noncanonical" pathways, leading to distinct patterns in the individual subunits activated and downstream genetic responses produced. The canonical pathway involves activating the IκlB kinase (IKK) with subsequent phosphorylation-induced proteolysis of the IκBα inhibitors and consequent nuclear translocation of the Rel A transcriptional activator. Recent work using high-density oligonucleotide arrays have begun to systematically dissect the scope of the gene network under canonical NF-κB control and have yielded important insights into biological pathways controlled by it. This pathway controls expression of noncontiguous, functionally discrete groups of genes ("regulons"), whose temporal expression occurs in waves. Moreover, its mode of activation (oscillatory or monophasic) plays an important role in determining the spectrum of target genes expressed. By contrast, the noncanonical NF-κB activation pathway involves activating the NF-κB inducing kinase (NIK) to stimulate IKKα-induced phosphorylation and proteolytic processing of the 100-kDa cytoplasmic NF-κB2 precursor. Activated NF-κB2 then forms a complex with Rel B and NIK to translocate into the nucleus thereby activating a distinct set of genes. Although the noncanonical pathway has been most clearly linked to control of adaptive immunity, recent intriguing studies have implicated this pathway in viral induced stress response and in the metabolic syndrome. In this way, a single family of transcription factors can respond to diverse stimuli to regulate cardiovascular homeostasis.

Original languageEnglish (US)
Pages (from-to)111-130
Number of pages20
JournalCardiovascular Toxicology
Volume6
Issue number2
DOIs
StatePublished - Jun 2006

Fingerprint

Phosphotransferases
Genes
Gene Regulatory Networks
Transcription Factors
Phosphorylation
Chemical activation
Regulon
Physiological Stress
Viral DNA
Adaptive Immunity
Virus Diseases
Oligonucleotide Array Sequence Analysis
Cell Wall
Proteolysis
DNA Damage
Dissection
Reactive Oxygen Species
Homeostasis
Cytokines
Inflammation

Keywords

  • Canonical pathway
  • Gene networks
  • IκB kinase (IKK)
  • IKKγ
  • NF-κB-inducing kinase (NIK)
  • NF-κB/Rel A
  • Noncanonical pathway
  • Nuclear factor-κB essential modulator (NEMO)

ASJC Scopus subject areas

  • Toxicology
  • Cardiology and Cardiovascular Medicine

Cite this

The NF-κB regulatory network. / Brasier, Allan R.

In: Cardiovascular Toxicology, Vol. 6, No. 2, 06.2006, p. 111-130.

Research output: Contribution to journalArticle

Brasier, Allan R. / The NF-κB regulatory network. In: Cardiovascular Toxicology. 2006 ; Vol. 6, No. 2. pp. 111-130.
@article{e5aa20781290424894f16679abb003f1,
title = "The NF-κB regulatory network",
abstract = "Nuclear factor (NF)-κB is a family of seven structurally related transcription factors that play a central role in cardiovascular growth, stress response, and inflammation by controlling gene network expression. Although the NF- κB subunits are ubiquitously expressed, their actions are regulated in a celltype and stimulus-specific manner, allowing for a diverse spectrum of effects. For example, NF-κlB is activated by cytokines, reactive oxygen species, bacterial cell wall products, vasopressors, viral infection, and DNA damage. Recent molecular dissection of its mechanisms for activation has shown that NF-κlB can be induced by the so-called {"}canonical{"} and {"}noncanonical{"} pathways, leading to distinct patterns in the individual subunits activated and downstream genetic responses produced. The canonical pathway involves activating the IκlB kinase (IKK) with subsequent phosphorylation-induced proteolysis of the IκBα inhibitors and consequent nuclear translocation of the Rel A transcriptional activator. Recent work using high-density oligonucleotide arrays have begun to systematically dissect the scope of the gene network under canonical NF-κB control and have yielded important insights into biological pathways controlled by it. This pathway controls expression of noncontiguous, functionally discrete groups of genes ({"}regulons{"}), whose temporal expression occurs in waves. Moreover, its mode of activation (oscillatory or monophasic) plays an important role in determining the spectrum of target genes expressed. By contrast, the noncanonical NF-κB activation pathway involves activating the NF-κB inducing kinase (NIK) to stimulate IKKα-induced phosphorylation and proteolytic processing of the 100-kDa cytoplasmic NF-κB2 precursor. Activated NF-κB2 then forms a complex with Rel B and NIK to translocate into the nucleus thereby activating a distinct set of genes. Although the noncanonical pathway has been most clearly linked to control of adaptive immunity, recent intriguing studies have implicated this pathway in viral induced stress response and in the metabolic syndrome. In this way, a single family of transcription factors can respond to diverse stimuli to regulate cardiovascular homeostasis.",
keywords = "Canonical pathway, Gene networks, IκB kinase (IKK), IKKγ, NF-κB-inducing kinase (NIK), NF-κB/Rel A, Noncanonical pathway, Nuclear factor-κB essential modulator (NEMO)",
author = "Brasier, {Allan R.}",
year = "2006",
month = "6",
doi = "10.1385/CT:6:2:111",
language = "English (US)",
volume = "6",
pages = "111--130",
journal = "Cardiovascular Toxicology",
issn = "1530-7905",
publisher = "Humana Press",
number = "2",

}

TY - JOUR

T1 - The NF-κB regulatory network

AU - Brasier, Allan R.

PY - 2006/6

Y1 - 2006/6

N2 - Nuclear factor (NF)-κB is a family of seven structurally related transcription factors that play a central role in cardiovascular growth, stress response, and inflammation by controlling gene network expression. Although the NF- κB subunits are ubiquitously expressed, their actions are regulated in a celltype and stimulus-specific manner, allowing for a diverse spectrum of effects. For example, NF-κlB is activated by cytokines, reactive oxygen species, bacterial cell wall products, vasopressors, viral infection, and DNA damage. Recent molecular dissection of its mechanisms for activation has shown that NF-κlB can be induced by the so-called "canonical" and "noncanonical" pathways, leading to distinct patterns in the individual subunits activated and downstream genetic responses produced. The canonical pathway involves activating the IκlB kinase (IKK) with subsequent phosphorylation-induced proteolysis of the IκBα inhibitors and consequent nuclear translocation of the Rel A transcriptional activator. Recent work using high-density oligonucleotide arrays have begun to systematically dissect the scope of the gene network under canonical NF-κB control and have yielded important insights into biological pathways controlled by it. This pathway controls expression of noncontiguous, functionally discrete groups of genes ("regulons"), whose temporal expression occurs in waves. Moreover, its mode of activation (oscillatory or monophasic) plays an important role in determining the spectrum of target genes expressed. By contrast, the noncanonical NF-κB activation pathway involves activating the NF-κB inducing kinase (NIK) to stimulate IKKα-induced phosphorylation and proteolytic processing of the 100-kDa cytoplasmic NF-κB2 precursor. Activated NF-κB2 then forms a complex with Rel B and NIK to translocate into the nucleus thereby activating a distinct set of genes. Although the noncanonical pathway has been most clearly linked to control of adaptive immunity, recent intriguing studies have implicated this pathway in viral induced stress response and in the metabolic syndrome. In this way, a single family of transcription factors can respond to diverse stimuli to regulate cardiovascular homeostasis.

AB - Nuclear factor (NF)-κB is a family of seven structurally related transcription factors that play a central role in cardiovascular growth, stress response, and inflammation by controlling gene network expression. Although the NF- κB subunits are ubiquitously expressed, their actions are regulated in a celltype and stimulus-specific manner, allowing for a diverse spectrum of effects. For example, NF-κlB is activated by cytokines, reactive oxygen species, bacterial cell wall products, vasopressors, viral infection, and DNA damage. Recent molecular dissection of its mechanisms for activation has shown that NF-κlB can be induced by the so-called "canonical" and "noncanonical" pathways, leading to distinct patterns in the individual subunits activated and downstream genetic responses produced. The canonical pathway involves activating the IκlB kinase (IKK) with subsequent phosphorylation-induced proteolysis of the IκBα inhibitors and consequent nuclear translocation of the Rel A transcriptional activator. Recent work using high-density oligonucleotide arrays have begun to systematically dissect the scope of the gene network under canonical NF-κB control and have yielded important insights into biological pathways controlled by it. This pathway controls expression of noncontiguous, functionally discrete groups of genes ("regulons"), whose temporal expression occurs in waves. Moreover, its mode of activation (oscillatory or monophasic) plays an important role in determining the spectrum of target genes expressed. By contrast, the noncanonical NF-κB activation pathway involves activating the NF-κB inducing kinase (NIK) to stimulate IKKα-induced phosphorylation and proteolytic processing of the 100-kDa cytoplasmic NF-κB2 precursor. Activated NF-κB2 then forms a complex with Rel B and NIK to translocate into the nucleus thereby activating a distinct set of genes. Although the noncanonical pathway has been most clearly linked to control of adaptive immunity, recent intriguing studies have implicated this pathway in viral induced stress response and in the metabolic syndrome. In this way, a single family of transcription factors can respond to diverse stimuli to regulate cardiovascular homeostasis.

KW - Canonical pathway

KW - Gene networks

KW - IκB kinase (IKK)

KW - IKKγ

KW - NF-κB-inducing kinase (NIK)

KW - NF-κB/Rel A

KW - Noncanonical pathway

KW - Nuclear factor-κB essential modulator (NEMO)

UR - http://www.scopus.com/inward/record.url?scp=33847112418&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33847112418&partnerID=8YFLogxK

U2 - 10.1385/CT:6:2:111

DO - 10.1385/CT:6:2:111

M3 - Article

VL - 6

SP - 111

EP - 130

JO - Cardiovascular Toxicology

JF - Cardiovascular Toxicology

SN - 1530-7905

IS - 2

ER -