NFkB
Transcription Factors

Author: Gianpiero Pescarmona
Date: 08/07/2008

Description

DEFINITION

NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) is a protein complex that controls the transcription of genes involved in cytokine production, cellular adhesion, inflammation and apoptosis.

NF-κB is found in almost all animal cell types and is involved in cellular responses to stimuli such as stress, cytokines, free radicals, ultraviolet irradiation, oxidized LDL, and bacterial or viral antigens.
more details on the Signaling Pathways

DatabaseLink
WikigenesNFKB1NFKB2p65
GeneCardsNFKB1NFKB2"p65":
iHOPNFKB1NFKB2p65
OMIMNFKB1NFKB2"p65":
Entrez GeneNFKB1NFKB2"p65":

CHEMICAL STRUCTURE AND IMAGES

In mammals, the NFkB family is composed of five related transcription factors:

  • p50, p52 that are derived from larger precursors, p105 and p100, respectively
  • RelA (p65), c-Rel and RelB

that are active in the form of heterodimers

These transcription factors are related through an N-terminal, 300 amino acid, DNA binding/dimerization domain, called the Rel homology domain (RHD), through which they can form homodimers and heterodimers that bind to 9-10 base pair DNA sites, known as kB sites, in the promoters and enhancer regions of genes, thereby modulating gene expression.

  • p50 and p52 do not contain C-terminal TADs; therefore, p50 and p52 homodimers repress transcription unless they are bound to a protein containing a TAD, such as RelA, c-Rel or RelB or Bcl-3 (a related transcriptional co-activator).
  • RelA, c-Rel and RelB contain C-terminal transcriptional activation domains (TADs), which enable them to activate target gene expression.

h4 NFKB proteins homologies

NFkB is not synthesized de novo; therefore its transcriptional activity is silenced by interactions with inhibitory IkB proteins present in the cytoplasm.

There are currently seven identified IkB family members -

  • IkBa, IkBb,
  • Bcl-3,
  • IkBe,
  • IkBg
  • the precursor proteins p100 and p105

which are characterized by the presence of ankyrin repeats.

When relevant for the function

  • Primary structure
  • Secondary structure
  • Tertiary structure
  • Quaternary structure

SYNTHESIS AND TURNOVER

mRNA synthesis
protein synthesis
post-translational modifications
degradation

CELLULAR FUNCTIONS

cellular localization,
biological function

Downstream Targets

Among the molecules induced by NF-kB are cytokines, chemokines, effector molecules of immunity and pro-survival factors. The pro-survival effects of NF-kB can counter otherwise apoptotic signals coming from cytokine receptors such as TNF receptor I, which we discuss later, and can also protect stressed cells (this can be a factor limiting the effectiveness of cancer chemotherapeutic agents). Mutations that inactivate NF-kB are generally lethal because of the essential role of this protein in cell survival. Partial loss of function causes varying degrees of immunodeficiency: humans with such mutations have variable levels of immunodeficiency and many show poor inflammatory responses and lack some types of antibodies. These symptoms reflect the roles of NF-kB in innate immunity to bacteria (presumably via TLRs), inflammatory gene expression and B cell antigen receptor signaling.

NF-kB activates inflammatory gene expression
, which we discuss next, as well as in the diverse responses to other signals operating through the TNF receptor superfamily. It is also essential for responses to signaling through the variable antigen receptors of lymphocytes, which we describe later in the book. We shall see later in this section that although the protein is always called NF-kB, it is a group of related homodimeric and heterodimeric transcription factors that are likely to activate distinct sets of target genes.

REGULATION

Upstream Signal Transduction of NF-kB Activation

Regulation of nuclear factor kB activation

  • stress
  • cytokines
  • free radicals
  • ultraviolet irradiation
  • oxidized LDL
  • bacterial or viral antigens

Fig1

Homocysteine stimulates nuclear factor kappaB activity and monocyte chemoattractant protein-1 expression in vascular smooth-muscle cells: a possible role for protein kinase C.

ROS

Nucling

Nucling mediates apoptosis by inhibiting expression of galectin-3 through interference with nuclear factor kB signalling 2004

c-IAP2 and TRAF: their role in apoptosis

Negative regulation of toll-like receptor signaling by NF-kappaB p50 ubiquitination blockade.

Canonical and non-canonical NFKB activation pathways

the Alternative (TRAF) Pathway

NF-kB and RelB

NF-kB activation by Nicotine

Progress of the study of rho-kinase and future perspective of the inhibitor. 2007

Prenatal nicotine exposure increases connective tissue expression in foetal monkey pulmonary vessels. 2004

NF-kB activation by TNF via ATF3

NKAP is an activator of NFkB that mediated TNF action

NKAP

Identification of a nuclear protein that promotes NF-kappaB activation. 2003
Biochem Biophys Res Commun. 2003 Oct 24;310(3):720-4.
Chen D, Li Z, Yang Q, Zhang J, Zhai Z, Shu HB.

Department of Cell Biology and Genetics, College of Life Sciences, Peking University, Beijing, China.
Abstract

Receptor-interacting protein (RIP) is a serine/threonine protein kinase that is critically involved in tumor necrosis factor receptor-1 (TNF-R1)-induced NF-kappaB activation. In a yeast two-hybrid screening for potential RIP-interacting proteins, we identified a novel protein designated as NKAP. Although NKAP interacts with RIP in yeast, NKAP does not interact with RIP in mammalian cells in co-immunoprecipitation experiments. When overexpressed in 293 cells, NKAP activated NF-kappaB in a dose-dependent manner. Moreover, down-regulation of NKAP by antisense RNA significantly inhibited TNF- and IL-1-induced NF-kappaB activation. Immunofluorescent staining indicated that NKAP was localized in the nucleus. Our findings suggest that NKAP is a novel nuclear regulator of TNF- and IL-1-induced NF-kappaB activation.

Comments
2014-07-02T19:04:30 - Sabatina Liuni

The canonical and noncanonical pathways
The system is mainly regulated by a multimeric IkappaB kinase (IKK) complex made up of two catalytic subunits, called inhibitors of kappa kinase alpha and beta (IKKα and IKKβ) and of a regulatory unit (IKKγ), also called NF-kB essential modulator, or NEMO. NEMO syndrome (incontinentia pigmenti) and systemic lupus erythematosus: a new disease association.,2012
Activation of NF-κB results in nuclear translocation and can proceed either through classical/canonical or alternative/noncanonical and hybrid pathways.
The canonical pathway is also called the classical pathway and works by recognizing a ligand which starts a signaling cascade downstream. This signaling cascade leads to activation of Iκκβ which is complexed together with Iκκα and Iκκγ. NF-κB and systemic lupus erythematosus: examining the link., 2013
Iκκβ is phosphorylated by either transautophosphorylation or TAK1 and MEKK3. LUBAC (Linear UBiquitin chain Assembly Complex) - mediated nondegradative linear polyubiquitination of NF-κB essential modulator is required for IKKβ phosphorylation. NF-kappaB in renal inflammation.,2010
In its resting state, NF-κB is located in the cytosol bound to IκB proteins, including IκBα, IκBβ, IκBε and IκBζ, which inactivate the NF-κB subunits. The activation of Iκκβ leads to the phosphorylation of IκB proteins which results in ubiquitination and eventual degradation by the proteosome. p50-RelA heterodimers translocate to the nucleus where it leads to up-regulated transcription of a variety of target genes.
The noncanonical pathway is controlled by particular members of the tumor necrosis factor (TNF) cytokine family, which include BAFF, CD40 ligand and lymphotoxin-β (LTβ). Activation of Iκκα by a MAP3K (NF-κB–inducing kinase, NIK) leads to the generation of p52/RelB complexes as a result of the phosphorylation of p100 (the precursor of p52). From there, transcription is regulated as in the classical pathway. The non-canonical pathway is independent of Iκκβ and Iκκγ. NF-κB and systemic lupus erythematosus: examining the link., 2013

Attachments
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NF-kB.jpgmonica22/07/2008
nfkb-600.gifgp25/11/2009
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