IKK-β also known as inhibitor of nuclear factor kappa-B kinase subunit beta is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...

that in humans is encoded by the ''IKBKB'' (inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase beta)

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...

Function

IKK-β is an

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...

that serves as a

subunit of

IκB kinase The IκB kinase (IkappaB kinase or IKK) is an enzyme complex that is involved in propagating the cellular response to inflammation. The IκB kinase enzyme complex is part of the upstream NF-κB signal transduction cascade. The IκBα (inhibitor ...

, which is a component of the

cytokine Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...

-activated

intracellular signaling In biology, cell signaling (cell signalling in British English) or cell communication is the ability of a cell to receive, process, and transmit signals with its environment and with itself. Cell signaling is a fundamental property of all cellula ...

pathway involved in triggering

immune responses An immune response is a reaction which occurs within an organism for the purpose of defending against foreign invaders. These invaders include a wide variety of different microorganisms including viruses, bacteria, parasites, and fungi which could ...

. IKK's activity causes activation of a

transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fu ...

known as Nuclear Transcription factor kappa-B or

NF-κB Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a protein complex that controls transcription of DNA, cytokine production and cell survival. NF-κB is found in almost all animal cell types and is involved in cellular ...

. Activated IKK-β

phosphorylates In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, whi ...

a protein called the ''

inhibitor Inhibitor or inhibition may refer to: In biology * Enzyme inhibitor, a substance that binds to an enzyme and decreases the enzyme's activity * Reuptake inhibitor, a substance that increases neurotransmission by blocking the reuptake of a neurotra ...

of NF-κB'', IκB (

IκBα IκBα (nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha) is one member of a family of cellular proteins that function to inhibit the NF-κB transcription factor. IκBα inhibits NF-κB by masking the nuclear lo ...

), which binds NF-κB to inhibit its function. Phosphorylated IκB is degraded via the

ubiquitin Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ''ubiquitously''. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 1980s. Fo ...

ation pathway, freeing NF-κB, and allowing its entry into the

nucleus Nucleus ( : nuclei) is a Latin word for the seed inside a fruit. It most often refers to: *Atomic nucleus, the very dense central region of an atom *Cell nucleus, a central organelle of a eukaryotic cell, containing most of the cell's DNA Nucle ...

of the cell where it activates various genes involved in

inflammation Inflammation (from la, wikt:en:inflammatio#Latin, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or Irritation, irritants, and is a protective response involving im ...

and other immune responses.

Clinical significance

IKK-β plays a significant role in

brain A brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as vision. It is the most complex organ in a v ...

cells Cell most often refers to: * Cell (biology), the functional basic unit of life Cell may also refer to: Locations * Monastic cell, a small room, hut, or cave in which a religious recluse lives, alternatively the small precursor of a monastery w ...

following a

stroke A stroke is a medical condition in which poor blood flow to the brain causes cell death. There are two main types of stroke: ischemic, due to lack of blood flow, and hemorrhagic, due to bleeding. Both cause parts of the brain to stop functionin ...

. If

activation by IKK-β is blocked, damaged cells within the brain stay alive, and according to a study performed by the

University of Heidelberg } Heidelberg University, officially the Ruprecht Karl University of Heidelberg, (german: Ruprecht-Karls-Universität Heidelberg; la, Universitas Ruperto Carola Heidelbergensis) is a public research university in Heidelberg, Baden-Württemberg, ...

and the University of Ulm, the cells even appear to make some recovery. Inhibition of IKK and IKK-related kinases has been investigated as a therapeutic option for the treatment of inflammatory diseases and cancer. The small-molecule inhibitor of IKK2 SAR113945, developed by Sanofi-Aventis, was evaluated in patients with knee osteoarthritis.

Model organisms

Model organism A model organism (often shortened to model) is a non-human species that is extensively studied to understand particular biological phenomena, with the expectation that discoveries made in the model organism will provide insight into the workin ...

s have been used in the study of IKK-β function. The size of an

infarct Infarction is tissue death (necrosis) due to Ischemia, inadequate blood supply to the affected area. It may be caused by Thrombosis, artery blockages, rupture, mechanical compression, or vasoconstriction. The resulting lesion is referred to as a ...

, or tissue killed or damaged by

ischemia Ischemia or ischaemia is a restriction in blood supply to any tissue, muscle group, or organ of the body, causing a shortage of oxygen that is needed for cellular metabolism (to keep tissue alive). Ischemia is generally caused by problems wi ...

, is reduced in mice in which IKK-β has been blocked. Additionally, experimental mice with an overactive form of IKK-β experience loss of many more neurons than normal mice after a stroke-simulating event. Researchers found a molecule that could block the signaling of IKK-β for up to four and a half hours. In another study, researchers found that inhibiting IKK-β prevented

kidney The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; blood ...

and

wasting disease In medicine, wasting, also known as wasting syndrome, refers to the process by which a debilitating disease causes muscle and fat tissue to "waste" away. Wasting is sometimes referred to as "acute malnutrition" because it is believed that epis ...

s in an

animal model An animal model (short for animal disease model) is a living, non-human, often genetic-engineered animal used during the research and investigation of human disease, for the purpose of better understanding the disease process without the risk of ha ...

used to study wasting diseases of human

AIDS Human immunodeficiency virus infection and acquired immunodeficiency syndrome (HIV/AIDS) is a spectrum of conditions caused by infection with the human immunodeficiency virus (HIV), a retrovirus. Following initial infection an individual m ...

sufferers. A conditional

knockout mouse A knockout mouse, or knock-out mouse, is a genetically modified mouse (''Mus musculus'') in which researchers have inactivated, or "knocked out", an existing gene by replacing it or disrupting it with an artificial piece of DNA. They are importan ...

line, called ''Ikbkb^{tm1a(EUCOMM)Wtsi}'' was generated as part of the

International Knockout Mouse Consortium The International Knockout Mouse Consortium (IKMC) is a scientific endeavour to produce a collection of mouse embryonic stem cell lines that together lack every gene in the genome, and then to distribute the cells to scientific researchers to crea ...

program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists — at the

Wellcome Trust Sanger Institute The Wellcome Sanger Institute, previously known as The Sanger Centre and Wellcome Trust Sanger Institute, is a non-profit British genomics and genetics research institute, primarily funded by the Wellcome Trust. It is located on the Wellcome G ...

. Male and female animals underwent a standardized

phenotypic screen In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology or physical form and structure, its developmental processes, its biochemical and physiological proper ...

to determine the effects of deletion. Twenty six tests were carried out and two

phenotypes In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology or physical form and structure, its developmental processes, its biochemical and physiological proper ...

were reported. A reduced number of

homozygous Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism. Mo ...

mutant In biology, and especially in genetics, a mutant is an organism or a new genetic character arising or resulting from an instance of mutation, which is generally an alteration of the DNA sequence of the genome or chromosome of an organism. It ...

embryos were identified during gestation, and none survived until

weaning Weaning is the process of gradually introducing an infant human or another mammal to what will be its adult diet while withdrawing the supply of its mother's milk. The process takes place only in mammals, as only mammals produce milk. The infan ...

. The remaining tests were carried out on

heterozygous Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism. Mo ...

mutant adult mice, and no significant abnormalities were observed in these animals.

Interactions

IKK-β (IKBKB) has been shown to

interact Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...

with *

HDAC9 Histone deacetylase 9 is an enzyme that in humans is encoded by the ''HDAC9'' gene. Function Histones play a critical role in transcriptional regulation, cell cycle progression, and developmental events. Histone acetylation/deacetylation alters ...

, *

CDC37 Hsp90 co-chaperone Cdc37 is a protein that in humans is encoded by the ''CDC37'' gene. The protein encoded by this gene is highly similar to Cdc 37, a cell division cycle control protein of Saccharomyces cerevisiae. This protein is a HSP90 Co- ...

, *

CHUK Inhibitor of nuclear factor kappa-B kinase subunit alpha (IKK-α) also known as IKK1 or conserved helix-loop-helix ubiquitous kinase (CHUK) is a protein kinase that in humans is encoded by the ''CHUK'' gene. IKK-α is part of the IκB kinase co ...

CTNNB1 Catenin beta-1, also known as beta-catenin (β-catenin), is a protein that in humans is encoded by the ''CTNNB1'' gene. Beta-catenin is a dual function protein, involved in regulation and coordination of cell–cell adhesion and gene transcripti ...

, *

FANCA Fanconi anaemia, complementation group A, also known as FAA, FACA and FANCA, is a protein which in humans is encoded by the ''FANCA'' gene. It belongs to the Fanconi anaemia complementation group (FANC) family of genes of which 12 complementation ...

, *

IKBKG NF-kappa-B essential modulator (NEMO) also known as inhibitor of nuclear factor kappa-B kinase subunit gamma (IKK-γ) is a protein that in humans is encoded by the ''IKBKG'' gene. NEMO is a subunit of the IκB kinase complex that activates NF-κB ...

IRAK1 Interleukin-1 receptor-associated kinase 1 (IRAK-1) is an enzyme in humans encoded by the ''IRAK1'' gene. IRAK-1 plays an important role in the regulation of the expression of inflammatory genes by immune cells, such as monocytes and macrophages, ...

, * NFKBIA, *

MAP3K14 Mitogen-activated protein kinase kinase kinase 14 also known as NF-kappa-B-inducing kinase (NIK) is an enzyme that in humans is encoded by the ''MAP3K14'' gene. Function This gene encodes mitogen-activated protein kinase kinase kinase 14, NIK, ...

, *

NFKB1 Nuclear factor NF-kappa-B p105 subunit is a protein that in humans is encoded by the ''NFKB1'' gene. This gene encodes a 105 kD protein which can undergo cotranslational processing by the 26S proteasome to produce a 50 kD protein. The 105 kD prot ...

, *

NFKBIB NF-kappa-B inhibitor beta is a protein that in humans is encoded by the ''NFKBIB'' gene. Function NFKB1 (MIM 164011) or NFKB2 (MIM 164012) is bound to REL (MIM 164910), RELA (MIM 164014), or RELB (MIM 604758) to form the NFKB complex. The NFKB ...

, *

NCOA3 The nuclear receptor coactivator 3 also known as NCOA3 is a protein that, in humans, is encoded by the ''NCOA3'' gene. NCOA3 is also frequently called 'amplified in breast 1' (AIB1), steroid receptor coactivator-3 (SRC-3), or thyroid hormone recept ...

, *

PPM1B Protein phosphatase 1B is an enzyme that in humans is encoded by the ''PPM1B'' gene. Function The protein encoded by this gene is a member of the PP2C family of Ser/Thr protein phosphatases. PP2C family members are known to be negative regulato ...

, *

TNFRSF1A Tumor necrosis factor receptor 1 (TNFR1), also known as tumor necrosis factor receptor superfamily member 1A (TNFRSF1A) and CD120a, is a ubiquitous membrane receptor that binds tumor necrosis factor-alpha (TNFα). Function The protein encoded b ...

, and *

TRAF2 TNF receptor-associated factor 2 is a protein that in humans is encoded by the ''TRAF2'' gene. Function The protein encoded by this gene is a member of the TNF receptor associated factor (TRAF) protein family. TRAF proteins associate with, an ...

Function

Clinical significance

Model organisms

Interactions

References

See also