Disease relevance of Spotlight

• Our findings support a functional relationship between Aurora kinase expression and prostate cancer and the application of small-molecule inhibitors in therapeutic modalities [1].
• A role for Aurora kinases in the aggressive behavior of mesotheliomas is of potential clinical interest because of the recent development of small-molecule inhibitors [2].
• This reinforces the concept of preferential dysregulation of the centrosome complex in CIN-type (aneuploid), compared with MIN-type, sporadic colorectal cancers and may influence the response to and efficiency of novel therapeutics targeting Aurora kinases [3].
• 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 [4].
• The expression at the protein level of all 3 Aurora kinases was significantly higher in 3 thyroid papillary carcinomas with respect to normal matched tissues obtained from the same patients [5].
• Aurora A and B expression was variable in primary breast tumors [6].

High impact information on Spotlight

• 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 [7].
• Evidence that the Ipl1-Sli15 (Aurora kinase-INCENP) complex promotes chromosome bi-orientation by altering kinetochore-spindle pole connections [8].
• In yeast, the ortholog of the Aurora B-INCENP protein kinase complex (Ipl1-Sli15) may have a role in this crucial process, because it is necessary to prevent attachment of sister kinetochores to microtubules from the same spindle pole [8].
• Polyadenylation is mediated by the phosphorylation of CPEB by Aurora, a kinase whose activity oscillates with the cell cycle [9].
• The Aurora kinases are essential for the regulation of chromosome segregation and cytokinesis during mitosis [10].

Chemical compound and disease context of Spotlight

• This month's Spotlight on... focuses on the current clinical development of the antiepileptic drug levetiracetam for amyotrophic lateral sclerosis [11].

Biological context of Spotlight

• Here we report the discovery of a highly potent and selective small-molecule inhibitor of Aurora kinases, VX-680, that blocks cell-cycle progression and induces apoptosis in a diverse range of human tumor types [10].
• Recent work on both kinases has revealed functional links between Aurora kinase activity and the mechanics of cell division [12].
• Here, we show that insulin also stimulates Aurora A-catalyzed CPEB S174 phosphorylation, cytoplasmic polyadenylation, translation, and oocyte maturation [13].
• Why do polyploid cells containing abnormal centrosome numbers induced by Aurora not get eliminated at cell-cycle checkpoints [14]?
• Here we show that by removal of small-molecule inhibitors, controlled activation of Aurora kinase during mitosis can correct chromosome attachment errors by selective disassembly of kinetochore-microtubule fibres, rather than by alternative mechanisms involving initial release of microtubules from either kinetochores or spindle poles [15].

Anatomical context of Spotlight

• The oncogenic protein kinase Aurora A is a critical regulator of meiotic and mitotic cell cycles in eukaryotic cells [16].
• Inhibition of Aurora kinases perturbs chromosome alignment and spindle checkpoint signaling in rat spermatocytes [17].
• To investigate the functions of Aurora kinases in male meiosis, we applied a small molecule Aurora inhibitor, ZM447439, to seminiferous tubules in vitro [17].
• Expression of Aurora kinases in human thyroid carcinoma cell lines and tissues [5].
• Moreover, to characterize the roles of each Aurora member, which share many similarities, we investigated the expression profiles of the family in normal tissues and a panel of different phases of the HeLa cell cycle [18].

Associations of Spotlight with other chemical compounds

• Polyadenylation is stimulated by Aurora A (Eg2)-catalyzed CPEB serine 174 phosphorylation, which occurs soon after oocytes are exposed to progesterone [13].
• These results suggest that the progesterone and insulin stimulate maturation by inhibiting GSK-3, which allows Aurora A activation and CPEB-mediated translation [13].
• AIM-1 and STK15 belong to the Aurora/increase-in-ploidy (Ipl)1 serine/threonine kinase family and play key roles in mitosis [19].
• Mutations in the yeast Aurora, Ipl1, are suppressed by overexpression of Glc8, the yeast homolog of phosphatase inhibitor-2 (I-2) [20].
• JNJ-7706621 is a novel cell cycle inhibitor that showed potent inhibition of several cyclin-dependent kinases (CDK) and Aurora kinases and selectively blocked proliferation of tumor cells of various origins but was about 10-fold less effective at inhibiting normal human cell growth in vitro [21].
• We show that this conserved serine on human TACC3 (Ser(558)) is also phosphorylated by Aurora A [22].

Gene context of Spotlight

• Genetic, biochemical, and microarray analyses suggest that APC-dependent cell cycle control of H3 phosphorylation is exerted at the level of an Aurora H3 kinase, Ipl1p, while APC-dependent transcriptional induction of GLC7, an essential H3 phosphatase, contributes to sustained H3 dephosphorylation upon cell cycle withdrawal [23].
• We have performed a detailed domain functional analysis of TPX2 and found that a large N-terminal domain containing the Aurora A binding peptide interacts directly with and nucleates microtubules in pure tubulin solutions [24].
• Moreover, Mob1p, but not Cdc15p, is required for dissociating Aurora from the kinetochore region [25].
• The recent determination of the three-dimensional structure of Aurora A has shown that Aurora kinases exhibit unique conformations around the activation loop region [26].
• The function of Aurora-C kinase, a member of the Aurora kinase family identified in mammals, is currently unknown [27].
• We report that heterologous expression of wild-type and kinase-inactive forms of TLK-1 suppresses the lethality of temperature-sensitive mutants of the yeast Aurora B kinase Ipl1 [28].

Analytical, diagnostic and therapeutic context of Spotlight

• The microinjection of Inh-2 restores Aurora activation, CPEB hyperphosphorylation and cyclin B translation in enucleated oocytes [29].
• Technological analysis of lithic artefacts recovered at the Aurora stratum of Atapuerca-TD6 shows that this Lower Pleistocene assemblage is similar to Mode I Technology (=Oldowan tradition) documented at many African sites [30].
• By RT-PCR analysis in various tissues, Aurora C-SV, like Aurora C, was found to be expressed at the highest level in human testis [31].
• The Aurora is a flexible platform that provides the desired renal therapy with ease of use and proper support for the hemodialysis patient when combined with Baxter's 24-hour infrastructure and support [32].
• The Aurora encoding protein was detected in COS-7 transfected with different Aurora transcripts by Western blot [33].

References