Aurora B kinase
Encyclopedia
Aurora B kinase is a protein
that functions in the attachment of the mitotic spindle
to the centromere
.
In cancerous cells, over-expression of these enzymes causes unequal distribution of genetic information, creating aneuploid
cells, a hallmark of cancer.
screen for kinases that are overexpressed in cancers. In the same year, rat Aurora kinase B was identified in a screen designed to find kinases that altered S. cerevisiae proliferation when overexpressed.
. Expression of Aurora B reaches a maximum at the G2-M transition, whereas Aurora B protein is most active during mitosis
.
Aurora B is a chromosomal passenger protein. Specifically, Aurora B localizes to the chromosomes in prophase
, the centromere
in prometaphase
and metaphase
, and the central mitotic spindle
in anaphase
. This localization has been determined by indirect immunofluorescence
in mammalian, C. elegans
, and Drosophila
cells. A more detailed analysis of Aurora B localization has been carried out in mammalian cells by tagging Aurora B with green fluorescent protein
. This analysis showed that the association of Aurora B with centromeres is dynamic (Aurora B at the centromere is constantly exchanging with a pool of cytoplasmic Aurora B). The analysis of tagged Aurora B also suggested that it associates with spindle microtubules during anaphase of mitosis and this association significantly limits its mobility. Finally, a portion of the tagged Aurora B localized to the equatorial cell cortex, having been transported to this location by astral microtubules
.
and INCENP
. Each of the three components of the complex is required for the proper localization and function of the other two. INCENP stimulates Aurora B kinase activity. Survivin might do the same.
Localization of Aurora B to the centromere during prometaphase and metaphase requires phosphorylation of the mammalian kinetochore
-specific histone
-H3 variant centromere protein A (CENP-A). CENP-A associates with the centromere and is necessary for assembly of the kinetochore. Phosphorylation of CENP-A at serine
7 by Aurora A kinase
recruits Aurora B to the centromere. Aurora B, itself, can also phosphorylate CENP-A at the same residue once it is recruited (see below).
Recently, topoisomerase II has been implicated in the regulation of Aurora B localization and enzymatic activity. This regulatory role may be directly associated with the role of topoisomerase II in disjoining sister chromatids
prior to anaphase. In topoisomerase II-depleted cells, Aurora B and INCENP do not transfer to the central spindle in late mitosis. Instead, they remain tightly associated with the centromeres of non-disjoined sister chromatids. Also, cells deficient in topoisomerase II show significantly reduced Aurora B kinase activity. Inhibition of Aurora B due to loss of topoisomerase II seems to depend on BubR1 activity (see below).
Aurora B has been shown to bind to end-binding protein 1 (EB1), a protein that regulates microtubule dynamics. Indirect immunofluorescence showed that Aurora B and EB1 colocalize during anaphase on the central spindle and in the midbody during cytokinesis
. Intriguingly, EB1 overexpression enhances Aurora B kinase activity, at least in part because EB1 blocks the dephosphorylation/inactivation of Aurora B by protein phosphatase 2A.
Inhibition of Aurora B function by RNA interference
or microinjection of blocking antibodies impairs the alignment of chromosomes at the equator of the mitotic spindle. This process of alignment is referred to as chromosome congression. The reason for this defect is a subject of ongoing study. Aurora B inhibition may lead to an increase in the number of syntelic
attachments (sister chromatid pairs in which both sister kinetochores are attached to microtubules radiating from the same spindle pole). Intriguingly, expression of a dominant-negative and catalytically inactive form of Aurora B disrupted microtuble attachment to the kinetochore and prevented the association of dynein
and centromere protein E
(CENP-E) with kinetochores.
Numerous kinetochore targets of Aurora kinases have been determined in organisms ranging from yeast to man. Most notably, CENP-A is a target of Aurora B. The phosphorylation of CENP-A by Aurora B reaches a maximum in prometaphase. In fact, Aurora A targets the same CENP-A phosphorylation site as Aurora B, and CENP-A phosphorylation by Aurora A is thought to precede that by Aurora B. Thus, a model has been proposed in which CENP-A phosphorylation by Aurora A recruits Aurora B to the centromere, the latter maintaining the phosphorylation state of CENP-A in a positive feedback
loop. Oddly, mutation of this phosphorylation site in CENP-A leads to defects in cytokinesis
.
Aurora B also interacts with mitotic centromere-associated kinesin (MCAK). Both Aurora B and MCAK localize to the inner centromere during prometaphase. Aurora B has been shown to recruit MCAK to the centromere and directly phosphorylate MCAK on various residues. Phosphorylation of MCAK by Aurora B limits the ability of MCAK to depolymerize microtubules. Importantly, inhibition of MCAK by a number of approaches leads to improper attachment of kinetochores to spindle microtubules.
It has been hypothesized that tension generated by amphitelic attachment (biorientation; the attachment of sister kinetochores to opposite spindle poles) pulls sister kinetochores apart, thus disrupting the interaction of Aurora B at the innermost portion of the centromere with microtubule binding sites on the fibrous corona of the outermost centromere. Specifically, the tension generated by biorientation pulls MCAK outside of the area of Aurora B localization. Thus, mitosis proceeds upon biorientation and dissociation of Aurora B from its substrates.
condensation. Though Aurora B is enriched at centromeres, it localizes diffusely to all chromatin.
In Drosophila cells, Aurora B depletion disrupts chromosome structure and compaction. In these cells, the condensin
complex does not localize appropriately to the chromosomes. Similarly, in C. elegans, condensin activity is dependent on Aurora B in metaphase. However, in Xenopus
cell extracts, condensin binding and chromosome condensation are independent of Aurora B. Likewise, after treating cells with an Aurora B enzyme inhibitor (Aurora B localization is not affected), the condensin complex localizes normally.
Aurora B localizes to the paired arms of homologous chromosomes in metaphase I of C. elegans meiosis
.and perturbs microtubule dynamics in mitosis. Release of this cohesion, which is dependent on Aurora B, is required for progression to anaphase I and segregation of homologous chromosomes. In mitotic vertebrate B lymphocytes, the proper centromeric localization of a number of Aurora B binding partners requires cohesin
.
in vertebrates, C. elegans
, Drosophila
, and fission yeast.
In various cell types, overexpression of a catalytically inactive Aurora B prevents cytokinesis. Disruption of cytokinesis can also arise from Aurora B mislocalization due to mutation of Aurora B binding partners.
Aurora B targets a number of proteins that localize to the cleavage furrow
, including the type-III intermediate filament
proteins vimentin
, desmin
, and glial fibrillary acidic protein (GFAP). In general, phosphorylation destabilizes intermediate filaments. Therefore, it has been proposed that phosphorylation of intermediate filaments at the cleavage furrow destabilizes the filaments in preparation for cytokinesis. In agreement with this hypothesis, mutation of Aurora B target sites in intermediate filament proteins leads to defects in filament deformation and prevents the final stage of cytokinesis.
Aurora B also phosphorylates myosin II regulatory light chain at the cleavage furrow. Inhibition of Aurora B activity prevents proper myosin II localization to the cleavage furrow and disrupts spindle midzone organization.
Aurora B may be involved in the localization of MAD2
and BubR1, proteins that recognize correct chromosome attachment to spindle microtubules. Loss of Aurora B lowers the concentration of Mad2 and BubR1 at the kinetochores. In particular, Aurora B seems to be responsible for maintaining the localization of Mad2 and BubR1 to the kinetochore following their initial recruitment, which occurs independent of Aurora B. Aurora B may be directly or indirectly involved in the hyper-phosphorylation of BubR1 seen in mitosis in wild-type cells.
with TACC1
, Survivin
, CDCA8
and BARD1
.
, which are both a cause and driver of cancer.
Inhibition of Aurora B kinase by BI811283
in cancer cells leads to the formation of cells with severely abnormal numbers of chromosomes (polyploid). Counterintuitively, inhibition of Aurora B kinase actually causes the polyploid cells formed to continue dividing however, because these cells have severe chromosomal abnormalities, they eventually stop dividing or undergo cell death.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
that functions in the attachment of the mitotic spindle
Mitotic spindle
In cell biology, the spindle fibers are the structure that separates the chromosomes into the daughter cells during cell division. It is part of the cytoskeleton in eukaryotic cells...
to the centromere
Centromere
A centromere is a region of DNA typically found near the middle of a chromosome where two identical sister chromatids come closest in contact. It is involved in cell division as the point of mitotic spindle attachment...
.
In cancerous cells, over-expression of these enzymes causes unequal distribution of genetic information, creating aneuploid
Aneuploidy
Aneuploidy is an abnormal number of chromosomes, and is a type of chromosome abnormality. An extra or missing chromosome is a common cause of genetic disorders . Some cancer cells also have abnormal numbers of chromosomes. Aneuploidy occurs during cell division when the chromosomes do not separate...
cells, a hallmark of cancer.
History
In 1998, Aurora kinase B was identified in humans by a polymerase chain reactionPolymerase chain reaction
The polymerase chain reaction is a scientific technique in molecular biology to amplify a single or a few copies of a piece of DNA across several orders of magnitude, generating thousands to millions of copies of a particular DNA sequence....
screen for kinases that are overexpressed in cancers. In the same year, rat Aurora kinase B was identified in a screen designed to find kinases that altered S. cerevisiae proliferation when overexpressed.
Expression and subcellular localization
The expression and activity of Aurora B are regulated according to the cell cycleCell cycle
The cell cycle, or cell-division cycle, is the series of events that takes place in a cell leading to its division and duplication . In cells without a nucleus , the cell cycle occurs via a process termed binary fission...
. Expression of Aurora B reaches a maximum at the G2-M transition, whereas Aurora B protein is most active during mitosis
Mitosis
Mitosis is the process by which a eukaryotic cell separates the chromosomes in its cell nucleus into two identical sets, in two separate nuclei. It is generally followed immediately by cytokinesis, which divides the nuclei, cytoplasm, organelles and cell membrane into two cells containing roughly...
.
Aurora B is a chromosomal passenger protein. Specifically, Aurora B localizes to the chromosomes in prophase
Prophase
Prophase, from the ancient Greek πρό and φάσις , is a stage of mitosis in which the chromatin condenses into a highly ordered structure called a chromosome in which the chromatin becomes visible. This process, called chromatin condensation, is mediated by the condensin complex...
, the centromere
Centromere
A centromere is a region of DNA typically found near the middle of a chromosome where two identical sister chromatids come closest in contact. It is involved in cell division as the point of mitotic spindle attachment...
in prometaphase
Prometaphase
Prometaphase is the phase of mitosis following prophase and preceding metaphase, in eukaryotic somatic cells. In Prometaphase, The nuclear envelope breaks into fragments and disappears. The tiny nucleolus inside the nuclear envolope, also dissolves. Microtubules emerging from the centrosomes at the...
and metaphase
Metaphase
Metaphase, from the ancient Greek μετά and φάσις , is a stage of mitosis in the eukaryotic cell cycle in which condensed & highly coiled chromosomes, carrying genetic information, align in the middle of the cell before being separated into each of the two daughter cells...
, and the central mitotic spindle
Mitotic spindle
In cell biology, the spindle fibers are the structure that separates the chromosomes into the daughter cells during cell division. It is part of the cytoskeleton in eukaryotic cells...
in anaphase
Anaphase
Anaphase, from the ancient Greek ἀνά and φάσις , is the stage of mitosis or meiosis when chromosomes move to opposite poles of the cell....
. This localization has been determined by indirect immunofluorescence
Immunofluorescence
Immunofluorescence is a technique used for light microscopy with a fluorescence microscope and is used primarily on biological samples. This technique uses the specificity of antibodies to their antigen to target fluorescent dyes to specific biomolecule targets within a cell, and therefore allows...
in mammalian, C. elegans
Caenorhabditis elegans
Caenorhabditis elegans is a free-living, transparent nematode , about 1 mm in length, which lives in temperate soil environments. Research into the molecular and developmental biology of C. elegans was begun in 1974 by Sydney Brenner and it has since been used extensively as a model...
, and Drosophila
Drosophila melanogaster
Drosophila melanogaster is a species of Diptera, or the order of flies, in the family Drosophilidae. The species is known generally as the common fruit fly or vinegar fly. Starting from Charles W...
cells. A more detailed analysis of Aurora B localization has been carried out in mammalian cells by tagging Aurora B with green fluorescent protein
Green fluorescent protein
The green fluorescent protein is a protein composed of 238 amino acid residues that exhibits bright green fluorescence when exposed to blue light. Although many other marine organisms have similar green fluorescent proteins, GFP traditionally refers to the protein first isolated from the...
. This analysis showed that the association of Aurora B with centromeres is dynamic (Aurora B at the centromere is constantly exchanging with a pool of cytoplasmic Aurora B). The analysis of tagged Aurora B also suggested that it associates with spindle microtubules during anaphase of mitosis and this association significantly limits its mobility. Finally, a portion of the tagged Aurora B localized to the equatorial cell cortex, having been transported to this location by astral microtubules
Astral microtubules
Astral microtubules are a subpopulation of microtubules, which only exist during and immediately before mitosis. They are defined as any microtubule originating from the centrosome which does not connect to a kinetochore. Astral microtubules develop in the actin skeleton and interact with the cell...
.
Regulation of Aurora B
Aurora B complexes with two other proteins, SurvivinSurvivin
Survivin, also called baculoviral inhibitor of apoptosis repeat-containing 5 or BIRC5, is a protein that, in humans, is encoded by the BIRC5 gene....
and INCENP
INCENP
Inner centromere protein is a protein that in humans is encoded by the INCENP gene.In mammalian cells, two broad groups of centromere-interacting proteins have been described: constitutively binding centromere proteins and 'passenger' proteins...
. Each of the three components of the complex is required for the proper localization and function of the other two. INCENP stimulates Aurora B kinase activity. Survivin might do the same.
Localization of Aurora B to the centromere during prometaphase and metaphase requires phosphorylation of the mammalian kinetochore
Kinetochore
The kinetochore is the protein structure on chromatids where the spindle fibers attach during cell division to pull sister chromatids apart....
-specific histone
Histone
In biology, histones are highly alkaline proteins found in eukaryotic cell nuclei that package and order the DNA into structural units called nucleosomes. They are the chief protein components of chromatin, acting as spools around which DNA winds, and play a role in gene regulation...
-H3 variant centromere protein A (CENP-A). CENP-A associates with the centromere and is necessary for assembly of the kinetochore. Phosphorylation of CENP-A at serine
Serine
Serine is an amino acid with the formula HO2CCHCH2OH. It is one of the proteinogenic amino acids. By virtue of the hydroxyl group, serine is classified as a polar amino acid.-Occurrence and biosynthesis:...
7 by Aurora A kinase
Aurora A kinase
Aurora A kinase also known as serine/threonine-protein kinase 6 is an enzyme that in humans is encoded by the AURKA gene.Aurora A is a member of a family of mitotic serine/threonine kinases. It is implicated with important processes during mitosis and meiosis whose proper function is integral for...
recruits Aurora B to the centromere. Aurora B, itself, can also phosphorylate CENP-A at the same residue once it is recruited (see below).
Recently, topoisomerase II has been implicated in the regulation of Aurora B localization and enzymatic activity. This regulatory role may be directly associated with the role of topoisomerase II in disjoining sister chromatids
Sister chromatids
Sister chromatids are two identical copies of a chromatid connected by a centromere. Compare sister chromatids to homologous chromosomes, which are the two different copies of the same chromosome that diploid organisms inherit, one from each parent...
prior to anaphase. In topoisomerase II-depleted cells, Aurora B and INCENP do not transfer to the central spindle in late mitosis. Instead, they remain tightly associated with the centromeres of non-disjoined sister chromatids. Also, cells deficient in topoisomerase II show significantly reduced Aurora B kinase activity. Inhibition of Aurora B due to loss of topoisomerase II seems to depend on BubR1 activity (see below).
Aurora B has been shown to bind to end-binding protein 1 (EB1), a protein that regulates microtubule dynamics. Indirect immunofluorescence showed that Aurora B and EB1 colocalize during anaphase on the central spindle and in the midbody during cytokinesis
Cytokinesis
Cytokinesis is the process in which the cytoplasm of a single eukaryotic cell is divided to form two daughter cells. It usually initiates during the late stages of mitosis, and sometimes meiosis, splitting a binucleate cell in two, to ensure that chromosome number is maintained from one generation...
. Intriguingly, EB1 overexpression enhances Aurora B kinase activity, at least in part because EB1 blocks the dephosphorylation/inactivation of Aurora B by protein phosphatase 2A.
Role in chromosome biorientation
Studies in several organisms indicate that Aurora B oversees chromosome biorientation by ensuring that appropriate connections are made between spindle microtubules and kinetochores.Inhibition of Aurora B function by RNA interference
RNA interference
RNA interference is a process within living cells that moderates the activity of their genes. Historically, it was known by other names, including co-suppression, post transcriptional gene silencing , and quelling. Only after these apparently unrelated processes were fully understood did it become...
or microinjection of blocking antibodies impairs the alignment of chromosomes at the equator of the mitotic spindle. This process of alignment is referred to as chromosome congression. The reason for this defect is a subject of ongoing study. Aurora B inhibition may lead to an increase in the number of syntelic
Syntelic
Syntelic attachment occurs when both sister chromosomes are attached to a single spindle pole....
attachments (sister chromatid pairs in which both sister kinetochores are attached to microtubules radiating from the same spindle pole). Intriguingly, expression of a dominant-negative and catalytically inactive form of Aurora B disrupted microtuble attachment to the kinetochore and prevented the association of dynein
Dynein
Dynein is a motor protein in cells which converts the chemical energy contained in ATP into the mechanical energy of movement. Dynein transports various cellular cargo by "walking" along cytoskeletal microtubules towards the minus-end of the microtubule, which is usually oriented towards the cell...
and centromere protein E
Centromere protein E
Centromere-associated protein E is a protein that in humans is encoded by the CENPE gene.-Further reading:...
(CENP-E) with kinetochores.
Numerous kinetochore targets of Aurora kinases have been determined in organisms ranging from yeast to man. Most notably, CENP-A is a target of Aurora B. The phosphorylation of CENP-A by Aurora B reaches a maximum in prometaphase. In fact, Aurora A targets the same CENP-A phosphorylation site as Aurora B, and CENP-A phosphorylation by Aurora A is thought to precede that by Aurora B. Thus, a model has been proposed in which CENP-A phosphorylation by Aurora A recruits Aurora B to the centromere, the latter maintaining the phosphorylation state of CENP-A in a positive feedback
Positive feedback
Positive feedback is a process in which the effects of a small disturbance on a system include an increase in the magnitude of the perturbation. That is, A produces more of B which in turn produces more of A. In contrast, a system that responds to a perturbation in a way that reduces its effect is...
loop. Oddly, mutation of this phosphorylation site in CENP-A leads to defects in cytokinesis
Cytokinesis
Cytokinesis is the process in which the cytoplasm of a single eukaryotic cell is divided to form two daughter cells. It usually initiates during the late stages of mitosis, and sometimes meiosis, splitting a binucleate cell in two, to ensure that chromosome number is maintained from one generation...
.
Aurora B also interacts with mitotic centromere-associated kinesin (MCAK). Both Aurora B and MCAK localize to the inner centromere during prometaphase. Aurora B has been shown to recruit MCAK to the centromere and directly phosphorylate MCAK on various residues. Phosphorylation of MCAK by Aurora B limits the ability of MCAK to depolymerize microtubules. Importantly, inhibition of MCAK by a number of approaches leads to improper attachment of kinetochores to spindle microtubules.
It has been hypothesized that tension generated by amphitelic attachment (biorientation; the attachment of sister kinetochores to opposite spindle poles) pulls sister kinetochores apart, thus disrupting the interaction of Aurora B at the innermost portion of the centromere with microtubule binding sites on the fibrous corona of the outermost centromere. Specifically, the tension generated by biorientation pulls MCAK outside of the area of Aurora B localization. Thus, mitosis proceeds upon biorientation and dissociation of Aurora B from its substrates.
Role in chromosome condensation and chromosome cohesion
Aurora B is responsible for phosphorylation of histone-H3 on serine 10 during mitosis. This modification is conserved from yeast (where the kinase is known as Ipl1) to man. Notably, histone-H3 phosphorylation by Aurora B seems not to be responsible for chromatinChromatin
Chromatin is the combination of DNA and proteins that make up the contents of the nucleus of a cell. The primary functions of chromatin are; to package DNA into a smaller volume to fit in the cell, to strengthen the DNA to allow mitosis and meiosis and prevent DNA damage, and to control gene...
condensation. Though Aurora B is enriched at centromeres, it localizes diffusely to all chromatin.
In Drosophila cells, Aurora B depletion disrupts chromosome structure and compaction. In these cells, the condensin
Condensin
Condensins are large protein complexes that play a central role in chromosome assembly and segregation in eukaryotic cells.- Subunit composition :...
complex does not localize appropriately to the chromosomes. Similarly, in C. elegans, condensin activity is dependent on Aurora B in metaphase. However, in Xenopus
Xenopus
Xenopus is a genus of highly aquatic frogs native to Sub-Saharan Africa. There are 19 species in the Xenopus genus...
cell extracts, condensin binding and chromosome condensation are independent of Aurora B. Likewise, after treating cells with an Aurora B enzyme inhibitor (Aurora B localization is not affected), the condensin complex localizes normally.
Aurora B localizes to the paired arms of homologous chromosomes in metaphase I of C. elegans meiosis
Meiosis
Meiosis is a special type of cell division necessary for sexual reproduction. The cells produced by meiosis are gametes or spores. The animals' gametes are called sperm and egg cells....
.and perturbs microtubule dynamics in mitosis. Release of this cohesion, which is dependent on Aurora B, is required for progression to anaphase I and segregation of homologous chromosomes. In mitotic vertebrate B lymphocytes, the proper centromeric localization of a number of Aurora B binding partners requires cohesin
Cohesin
Cohesin is a protein complex that regulates the separation of sister chromatids during cell division, either mitosis or meiosis.- Structure :...
.
Role in cytokinesis
The Aurora B complex is necessary for cytokinesisCytokinesis
Cytokinesis is the process in which the cytoplasm of a single eukaryotic cell is divided to form two daughter cells. It usually initiates during the late stages of mitosis, and sometimes meiosis, splitting a binucleate cell in two, to ensure that chromosome number is maintained from one generation...
in vertebrates, C. elegans
Caenorhabditis elegans
Caenorhabditis elegans is a free-living, transparent nematode , about 1 mm in length, which lives in temperate soil environments. Research into the molecular and developmental biology of C. elegans was begun in 1974 by Sydney Brenner and it has since been used extensively as a model...
, Drosophila
Drosophila melanogaster
Drosophila melanogaster is a species of Diptera, or the order of flies, in the family Drosophilidae. The species is known generally as the common fruit fly or vinegar fly. Starting from Charles W...
, and fission yeast.
In various cell types, overexpression of a catalytically inactive Aurora B prevents cytokinesis. Disruption of cytokinesis can also arise from Aurora B mislocalization due to mutation of Aurora B binding partners.
Aurora B targets a number of proteins that localize to the cleavage furrow
Cleavage furrow
In cell biology, the cleavage furrow is the indentation that begins the process of cleavage, by which animal and some algal cells undergo cytokinesis. The same proteins responsible for muscle contraction, actin and myosin begin the process of forming the cleavage furrow. This can only happen in...
, including the type-III intermediate filament
Intermediate filament
Intermediate filaments are a family of related proteins that share common structural and sequence features. Intermediate filaments have an average diameter of 10 nanometers, which is between that of 7 nm actin , and that of 25 nm microtubules, although they were initially designated...
proteins vimentin
Vimentin
Vimentin is a type III intermediate filament protein that is expressed in mesenchymal cells. IF proteins are found in all metazoan cells as well as bacteria. IF, along with tubulin-based microtubules and actin-based microfilaments, comprise the cytoskeleton...
, desmin
Desmin
Desmin is a protein that in humans is encoded by the DES gene.Desmin is a type III intermediate filament found near the Z line in sarcomeres. It was first described in 1976, first purified in 1977, the gene was cloned in 1989, and the first knock-out mouse was created in 1996. Desmin is only...
, and glial fibrillary acidic protein (GFAP). In general, phosphorylation destabilizes intermediate filaments. Therefore, it has been proposed that phosphorylation of intermediate filaments at the cleavage furrow destabilizes the filaments in preparation for cytokinesis. In agreement with this hypothesis, mutation of Aurora B target sites in intermediate filament proteins leads to defects in filament deformation and prevents the final stage of cytokinesis.
Aurora B also phosphorylates myosin II regulatory light chain at the cleavage furrow. Inhibition of Aurora B activity prevents proper myosin II localization to the cleavage furrow and disrupts spindle midzone organization.
Role in the spindle assembly checkpoint
The spindle assembly checkpoint inhibits progression of mitosis from metaphase to anaphase until all sister chromatid pairs are bioriented. Cells lacking Aurora B fail to arrest in metaphase even when chromosomes lack microtubule attachment. Consequently, Aurora B deficiency leads to progression through anaphase despite the presence of misaligned chromosomes.Aurora B may be involved in the localization of MAD2
MAD2
MAD2 is an essential spindle checkpoint protein. The spindle checkpoint system is a regulatory system that restrains progression through the metaphase-to-anaphase transition. The Mad2 gene was first identified in the yeast S. cerevisiae in a screen for genes which when mutated would confer...
and BubR1, proteins that recognize correct chromosome attachment to spindle microtubules. Loss of Aurora B lowers the concentration of Mad2 and BubR1 at the kinetochores. In particular, Aurora B seems to be responsible for maintaining the localization of Mad2 and BubR1 to the kinetochore following their initial recruitment, which occurs independent of Aurora B. Aurora B may be directly or indirectly involved in the hyper-phosphorylation of BubR1 seen in mitosis in wild-type cells.
Interactions
Aurora B kinase has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with TACC1
TACC1
Transforming acidic coiled-coil-containing protein 1 is a protein that in humans is encoded by the TACC1 gene.-Interactions:TACC1 has been shown to interact with Aurora A kinase, TDRD7, SNRPG, Aurora B kinase, LSM7, BARD1 and CKAP5.-Further reading:...
, Survivin
Survivin
Survivin, also called baculoviral inhibitor of apoptosis repeat-containing 5 or BIRC5, is a protein that, in humans, is encoded by the BIRC5 gene....
, CDCA8
CDCA8
Borealin is a protein that in humans is encoded by the CDCA8 gene.-Interactions:CDCA8 has been shown to interact with INCENP, Survivin and Aurora B kinase.-Further reading:...
and BARD1
BARD1
BRCA1-associated RING domain protein 1 is a protein that in humans is encoded by the BARD1 gene.-Interactions:BARD1 has been shown to interact with BRE, UBE2D1, CSTF2, BRCC3, RAD51, BCL3, TACC1, Ewing sarcoma breakpoint region 1, FANCD2, H2AFX, CSTF1, NPM1, BRCA2, BRCA1, P53 and Aurora B...
.
Role in cancer
Abnormally elevated levels of Aurora B kinase cause unequal chromosomal separation during cell division, resulting in the formation of cells with abnormal numbers of chromosomesAneuploidy
Aneuploidy is an abnormal number of chromosomes, and is a type of chromosome abnormality. An extra or missing chromosome is a common cause of genetic disorders . Some cancer cells also have abnormal numbers of chromosomes. Aneuploidy occurs during cell division when the chromosomes do not separate...
, which are both a cause and driver of cancer.
Inhibition of Aurora B kinase by BI811283
BI811283
BI 811283 is a small molecule inhibitor of the Aurora B kinase protein being developed by Boehringer Ingelheim for use as an anti-cancer agent. BI 811283 is currently in the early stages of clinical development and is undergoing first in human trials in patients with solid tumors and Acute Myeloid...
in cancer cells leads to the formation of cells with severely abnormal numbers of chromosomes (polyploid). Counterintuitively, inhibition of Aurora B kinase actually causes the polyploid cells formed to continue dividing however, because these cells have severe chromosomal abnormalities, they eventually stop dividing or undergo cell death.