Disease relevance of AURKB

• We have previously shown by microarray analysis of primary lung carcinomas and matched normal tissue that AURKB (22 out of 37) and AURKA (15 out of 37) transcripts are frequently over-represented in these tumours [1].
• Overexpression of aurora B kinase (AURKB) in primary non-small cell lung carcinoma is frequent, generally driven from one allele, and correlates with the level of genetic instability [1].
• Thus, the overexpression of AIM-1 in colorectal tumor cell lines is thought to have a causal relationship with multinuclearity and increased ploidy [2].
• In addition, nuclear expression of Aurora-B in prostatic intraepithelial neoplasia lesions correlated with clinical staging of the tumor (rho = -0.4, P = 0.0474) whereas cytoplasmic expression in tumors correlated with seminal vesicle invasion (rho = 0.282, P = 0.0098) [3].
• Here, we report that Aurora-A and Aurora-B are highly expressed in primary human and mouse prostate cancers and prostate cancer cell lines [3].

High impact information on AURKB

• Phosphorylation by Aurora B, which corrects improper kinetochore-microtubule connections in vivo, reduces the affinity of the Ndc80 complex for microtubules in vitro [4].
• The N terminus of Hec1 is phosphorylated by Aurora B kinase in vitro, and cells expressing N-terminal nonphosphorylatable mutants of Hec1 exhibit an increase in merotelic attachments, hyperstretching of centromeres, and errors in chromosome segregation [5].
• NoCut depends on the Aurora kinase Ipl1 and the anillin-related proteins Boi1 and Boi2, which localize to the site of cleavage in an Ipl1-dependent manner and act as abscission inhibitors [6].
• Here we report the identification of Dasra A and Dasra B, two new components of the vertebrate chromosomal passenger complex containing Incenp, Survivin, and the kinase Aurora B, and demonstrate that this complex is required for chromatin-induced microtubule stabilization and spindle formation [7].
• A novel histone deacetylase pathway regulates mitosis by modulating Aurora B kinase activity [8].

Chemical compound and disease context of AURKB

• The block of Aurora B expression induced by RNA interference or by using an inhibitor of Aurora kinase activity significantly reduced the growth of thyroid anaplastic carcinoma cells [9].
• Rebamipide inhibits gastric cancer growth by targeting survivin and Aurora-B [10].
• Significant reductions in growth were observed in Ark2 and KLE endometrial cancer cells following treatment with paclitaxel, doxorubicin, carboplatin, or the HDAC inhibitor trichostatin A (TSA) [11].

Biological context of AURKB

• Aurora B concentrates at centromeres in early G2, associates with histone H3 and centromeres at the times when histone H3 and CENP-A are phosphorylated, and phosphorylates histone H3 and CENP-A in vitro at a similar target serine residue [12].
• Mutation of threonine 117 to alanine prevents survivin phosphorylation by aurora-B in vitro but does not alter its localization in HeLa cells [13].
• Immunofluorescence analysis demonstrated that ARK2 was mainly localized to the midbody, while ARK1 has been reported to be localized to the spindle pole during mitosis [14].
• Cell cycle analysis revealed that the expression of ARK1 was correlated with G2/M phase, while ARK2 was expressed during S and G2/M phases [14].
• Aurora-C transcript is expressed at a moderate level albeit about an order of magnitude lower than Aurora-B transcript in diploid human fibroblasts [15].

Anatomical context of AURKB

• In these treated oocytes, no or only very weak AURKB activity and phosphorylation of histone H3 on Ser-10 can be detected after 27 h of treatment, whereas phosphorylation on Ser-28 is not influenced [16].
• The failure of microtubule stabilization caused by depletion of the chromosomal passenger complex was rescued by codepletion of the microtubule-depolymerizing kinesin MCAK, whose activity is negatively regulated by Aurora B [7].
• In a human interleukin-3-dependent cell line, F-36P, the expressions of AIM-1 and STK15 mRNA were specifically observed at G2/M phase of the cell cycle during proliferation [17].
• These results suggested that downregulation of AIM-1 at M phase may be involved in abortive mitosis and polyploid formation of megakaryocytes [17].
• Over expression of other mitotic kinases (Polo-like kinase 1 and Aurora-B) also causes multinucleation and concomitant increases in centrosome numbers [18].

Associations of AURKB with chemical compounds

• Here we report that human survivin is specifically phosphorylated in vitro by aurora-B kinase at threonine 117 in its carboxyl alpha-helical coil [13].
• Human Aurora/Ipl1-related kinase 2 (Aurora-B) is a key regulator of mitosis [19].
• Rebamipide significantly downregulates in AGS cell survivin expression, its association with Aurora-B and cell proliferation [10].
• Within the family, serine/threonine kinases (STK) have received comparatively lesser attention, vis-a-vis tyrosine kinases, in terms of their involvement in human cancers [20].
• Estrogen mediates phosphorylation of histone H3 in ovarian follicle and mammary epithelial tumor cells via the mitotic kinase, Aurora B [21].

Physical interactions of AURKB

• Human aurora-B binds to a proteasome alpha-subunit HC8 and undergoes degradation in a proteasome-dependent manner [19].
• These data suggest that Aurora B kinase activity and the formation of the Aurora B/INCENP/survivin complex both contribute to its proper localization [22].

Enzymatic interactions of AURKB

• We identified Ser-59 of desmin to be a specific site phosphorylated by Aurora-B in vitro [23].
• We report here that Aurora-B phosphorylates GFAP and desmin in vitro, and this phosphorylation leads to a reduction in filament forming ability [23].
• We also report that Aurora B phosphorylates MgcRacGAP on serine residues and that this modification induces latent GAP activity toward RhoA in vitro [24].
• We report here that human Aurora-B is phosphorylated at Thr-232 through interaction with the inner centromere protein (INCENP) in vivo [25].
• Here, we show that in C. elegans embryos and in cultured human cells, respectively, ZEN-4 and MKLP1 are phosphorylated by aurora B in vitro and in vivo on conserved C-terminal serine residues [26].

Regulatory relationships of AURKB

• Using recombinant proteins, we found that Aurora B kinase activity was stimulated by INCENP and that the C-terminal region of INCENP was sufficient for activation [22].
• Expression of a kinase-defective mutant of Aurora B disrupts cytokinesis and inhibits phosphorylation of MgcRacGAP at Ser387, but not its localization to the midbody [24].
• The results presented here suggest the possibility that Aurora-B may regulate cleavage furrow-specific phosphorylation and segregation of type III IFs coordinatedly with Rho-kinase during cytokinesis [23].
• Inactivation of aurora A activates checkpoint kinase BubR1 in an aurora B-dependent manner [27].
• We conclude that, as a key mitotic regulator, Aurora B is regulated both by its activation during early mitosis and by its destruction by APC/C-Cdh1 in late mitosis and in G1 [28].

Other interactions of AURKB

• We present evidence that Aurora-C, like Aurora-B kinase, is a chromosomal passenger protein localizing first to centromeres and then to the midzone of mitotic cells [15].
• A nonphosphorylatable mutant (TSS893-895AAA) was a poor activator of Aurora B, demonstrating that INCENP phosphorylation is important for kinase activation [22].
• We suggest therefore that the checkpoint is composed of two arms, one dependent on Bub1, the other on aurora B [29].
• Chromosomal passenger proteins including Aurora B, Survivin, and Borealin/Dasra B, also called CDCA8/FLJ10468, are known to play crucial roles during mitosis and cell division [30].
• Phosphorylation by aurora B converts MgcRacGAP to a RhoGAP during cytokinesis [24].

Analytical, diagnostic and therapeutic context of AURKB

• Real-time PCR analysis confirmed a strong expression of Aurora B in anaplastic thyroid carcinomas [9].
• Western blot was performed to determine the expression of survivin, Aurora B, phosphorylated-histone H3 (Ser 10), and caspase cleavage [31].
• In contrast, analysis of Aurora B and Anillin localization demonstrates that binucleation is characterized by asymmetric constriction, delay of furrow constriction and defective mid-body formation [32].
• MATERIALS AND METHODS: The expressions of Aurora-B and H3-P were examined in hepatocellular carcinoma (HCC) by immunohistochemistry [33].
• STK12 was mapped to human chromosome 17p13.1 by fluorescence in situ hybridization [34].

References