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1
Kim, Hyo Jin, and Jongchan Kim. "OTUD6A Is an Aurora Kinase A-Specific Deubiquitinase." International Journal of Molecular Sciences 22, no. 4 (February 16, 2021): 1936. http://dx.doi.org/10.3390/ijms22041936.
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Aurora kinases are serine/threonine kinases required for cell proliferation and are overexpressed in many human cancers. Targeting Aurora kinases has been a therapeutic strategy in cancer treatment. Here, we attempted to identify a deubiquitinase (DUB) that regulates Aurora kinase A (Aurora-A) protein stability and/or kinase activity as a potential cancer therapeutic target. Through pull-down assays with the human DUB library, we identified OTUD6A as an Aurora-A-specific DUB. OTUD6A interacts with Aurora-A through OTU and kinase domains, respectively, and deubiquitinates Aurora-A. Notably, OTUD6A promotes the protein half-life of Aurora-A and activates Aurora-A by increasing phosphorylation at threonine 288 of Aurora-A. From qPCR screening, we identified and validated that the cancer gene CKS2 encoding Cyclin-dependent kinases regulatory subunit 2 is the most upregulated cell cycle regulator when OTUD6A is overexpressed. The results suggest that OTUD6A may serve as a therapeutic target in human cancers.
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Qi, Guangying, Jing Liu, Sisi Mi, Takaaki Tsunematsu, Shengjian Jin, Wenhua Shao, Tian Liu, Naozumi Ishimaru, Bo Tang, and Yasusei Kudo. "Aurora Kinase Inhibitors in Head and Neck Cancer." Current Topics in Medicinal Chemistry 18, no. 3 (May 14, 2018): 199–213. http://dx.doi.org/10.2174/1568026618666180112163741.
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Aurora kinases are a group of serine/threonine kinases responsible for the regulation of mitosis. In recent years, with the increase in Aurora kinase-related research, the important role of Aurora kinases in tumorigenesis has been gradually recognized. Aurora kinases have been regarded as a new target for cancer therapy, resulting in the development of Aurora kinase inhibitors. The study and application of these small-molecule inhibitors, especially in combination with chemotherapy drugs, represent a new direction in cancer treatment. This paper reviews studies on Aurora kinases from recent years, including studies of their biological function, their relationship with tumor progression, and their inhibitors.
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Shi, Yijiang, Tony Reiman, Weiqun Li, Christopher Maxwell, Linda Pilarski, Rick Feldman, and Alan Lichtenstein. "Targeting Aurora Kinases as Therapy in Multiple Myeloma." Blood 108, no. 11 (November 16, 2006): 3484. http://dx.doi.org/10.1182/blood.v108.11.3484.3484.
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Abstract The aurora kinases A and B are critical for facilitating cell cycle transit from G2 through to cytokinesis. As important regulators of the mitotic event, they are being tested as potential targets in cancer therapy. Multiple myeloma (MM) is a B cell malignancy characterized by progressive genetic instability, suggesting a disruption of cell cycle checkpoints has occurred that normally arrest cells at G2M or within mitosis when injury to the mitotic machinery occurs. Since these deficient checkpoints would prevent cell cycle arrest and potential repair and may render MM cells susceptible to apoptotic death in mitosis, we tested the anti-myeloma effecy of two separate agents that inhibit aurora kinases. Both agents induced cytoreduction of MM cell lines and primary myeloma samples at nM concentrations while normal peripheral blood lymphocytes and CLL cells were not affected. MM cells were not protected by IL-6 or activating mutations of RAS. Anti-myeloma effects were characterized by induction of tetraploidy followed by apoptosis. The myeloma apoptotic effect correlated well with the inhibition of aurora kinase activity as shown by reduction of histone 3B phosphorylation (substrate of auroras). Furthermore, stable ectopic over-expression of aurora kinase A significantly protected MM cells against aurora inhibitors but had no effect on apoptosis induced by velcade. As expression of the centrosomal protein RHAMM in MM cells may contribute to genetic instability, we tested effects of RHAMM over-expression on the sensitivity to aurora inhibitors. Although RHAMM over-expression in transfected MM cells was very modest, it significantly enhanced sensitivity to apoptosis induced by aurora kinase inhibitors. These results suggest the potential for aurora kinase inhibitors in multiple myeloma especially in patients where RHAMM is over-expressed.
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Hochegger, Helfrid, Nadia Hégarat, and Jose B. Pereira-Leal. "Aurora at the pole and equator: overlapping functions of Aurora kinases in the mitotic spindle." Open Biology 3, no. 3 (March 2013): 120185. http://dx.doi.org/10.1098/rsob.120185.
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The correct assembly and timely disassembly of the mitotic spindle is crucial for the propagation of the genome during cell division. Aurora kinases play a central role in orchestrating bipolar spindle establishment, chromosome alignment and segregation. In most eukaryotes, ranging from amoebas to humans, Aurora activity appears to be required both at the spindle pole and the kinetochore, and these activities are often split between two different Aurora paralogues, termed Aurora A and B. Polar and equatorial functions of Aurora kinases have generally been considered separately, with Aurora A being mostly involved in centrosome dynamics, whereas Aurora B coordinates kinetochore attachment and cytokinesis. However, double inactivation of both Aurora A and B results in a dramatic synergy that abolishes chromosome segregation. This suggests that these two activities jointly coordinate mitotic progression. Accordingly, recent evidence suggests that Aurora A and B work together in both spindle assembly in metaphase and disassembly in anaphase. Here, we provide an outlook on these shared functions of the Auroras, discuss the evolution of this family of mitotic kinases and speculate why Aurora kinase activity may be required at both ends of the spindle microtubules.
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Pflug, Alexander, Taianá Maia de Oliveira, Dirk Bossemeyer, and Richard A. Engh. "Mutants of protein kinase A that mimic the ATP-binding site of Aurora kinase." Biochemical Journal 440, no. 1 (October 27, 2011): 85–93. http://dx.doi.org/10.1042/bj20110592.
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We describe in the present paper mutations of the catalytic subunit α of PKA (protein kinase A) that introduce amino acid side chains into the ATP-binding site and progressively transform the pocket to mimic that of Aurora protein kinases. The resultant PKA variants are enzymatically active and exhibit high affinity for ATP site inhibitors that are specific for Aurora kinases. These features make the Aurora-chimaeric PKA a valuable tool for structure-based drug discovery tasks. Analysis of crystal structures of the chimaera reveal the roles for individual amino acid residues in the binding of a variety of inhibitors, offering key insights into selectivity mechanisms. Furthermore, the high affinity for Aurora kinase-specific inhibitors, combined with the favourable crystallizability properties of PKA, allow rapid determination of inhibitor complex structures at an atomic resolution. We demonstrate the utility of the Aurora-chimaeric PKA by measuring binding kinetics for three Aurora kinase-specific inhibitors, and present the X-ray structures of the chimaeric enzyme in complex with VX-680 (MK-0457) and JNJ-7706621 [Aurora kinase/CDK (cyclin-dependent kinase) inhibitor].
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Deretic, Jovana, Alastair Kerr, and Julie P. I. Welburn. "A rapid computational approach identifies SPICE1 as an Aurora kinase substrate." Molecular Biology of the Cell 30, no. 3 (February 2019): 312–23. http://dx.doi.org/10.1091/mbc.e18-08-0495.
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Aurora kinases play a major role in mitosis by regulating diverse substrates. Defining their critical downstream targets is important in understanding Aurora kinase function. Here we have developed an unbiased computational approach to identify new Aurora kinase substrates based on phosphorylation site clustering, protein localization, protein structure, and species conservation. We validate the microtubule-associated proteins Clasp2, Elys, tubulin tyrosine ligase-like polyglutamylase residues 330–624 and spindle and centriole associated protein 1, residues 549–855 (SPICE1), as Aurora A and B kinases substrates in vitro. We also demonstrate that SPICE1 localization is regulated by Aurora kinases during mitosis. In the absence of Aurora kinase activity, SPICE1 remains at centrioles but does not target to the spindle. Similarly, a nonphosphorylatable SPICE1 mutant no longer localizes to the spindle. Finally, we show that misregulating SPICE1 phosphorylation results in abnormal centriole number, spindle multipolarity, and chromosome alignment defects. Overall, our work indicates that temporal and spatial Aurora kinase–mediated regulation of SPICE1 is important for correct chromosome segregation. In addition, our work provides a database-search tool that enables rapid identification of Aurora kinase substrates.
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Dvořák Tomaštíková, Eva, Twan Rutten, Petr Dvořák, Alisa Tugai, Klara Ptošková, Beáta Petrovská, Daniel van Damme, Andreas Houben, Jaroslav Doležel, and Dmitri Demidov. "Functional Divergence of Microtubule-Associated TPX2 Family Members in Arabidopsis thaliana." International Journal of Molecular Sciences 21, no. 6 (March 22, 2020): 2183. http://dx.doi.org/10.3390/ijms21062183.
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TPX2 (Targeting Protein for Xklp2) is an evolutionary conserved microtubule-associated protein important for microtubule nucleation and mitotic spindle assembly. The protein was described as an activator of the mitotic kinase Aurora A in humans and the Arabidopsis AURORA1 (AUR1) kinase. In contrast to animal genomes that encode only one TPX2 gene, higher plant genomes encode a family with several TPX2-LIKE gene members (TPXL). TPXL genes of Arabidopsis can be divided into two groups. Group A proteins (TPXL2, 3, 4, and 8) contain Aurora binding and TPX2_importin domains, while group B proteins (TPXL1, 5, 6, and 7) harbor an Xklp2 domain. Canonical TPX2 contains all the above-mentioned domains. We confirmed using in vitro kinase assays that the group A proteins contain a functional Aurora kinase binding domain. Transient expression of Arabidopsis TPX2-like proteins in Nicotiana benthamiana revealed preferential localization to microtubules and nuclei. Co-expression of AUR1 together with TPX2-like proteins changed the localization of AUR1, indicating that these proteins serve as targeting factors for Aurora kinases. Taken together, we visualize the various localizations of the TPX2-LIKE family in Arabidopsis as a proxy to their functional divergence and provide evidence of their role in the targeted regulation of AUR1 kinase activity.
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Li, Hui, Qian Chen, Markus Kaller, Wolfgang Nellen, Ralph Gräf, and Arturo De Lozanne. "Dictyostelium Aurora Kinase Has Properties of both Aurora A and Aurora B Kinases." Eukaryotic Cell 7, no. 5 (March 7, 2008): 894–905. http://dx.doi.org/10.1128/ec.00422-07.
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ABSTRACT Aurora kinases are highly conserved proteins with important roles in mitosis. Metazoans contain two kinases, Aurora A and B, which contribute distinct functions at the spindle poles and the equatorial region respectively. It is not currently known whether the specialized functions of the two kinases arose after their duplication in animal cells or were already present in their ancestral kinase. We show that Dictyostelium discoideum contains a single Aurora kinase, DdAurora, that displays characteristics of both Aurora A and B. Like Aurora A, DdAurora has an extended N-terminal domain with an A-box sequence and localizes at the spindle poles during early mitosis. Like Aurora B, DdAurora binds to its partner DdINCENP and localizes on centromeres at metaphase, the central spindle during anaphase, and the cleavage furrow at the end of cytokinesis. DdAurora also has several unusual properties. DdAurora remains associated with centromeres in anaphase, and this association does not require an interaction with DdINCENP. DdAurora then localizes at the cleavage furrow, but only at the end of cytokinesis. This localization is dependent on DdINCENP and the motor proteins Kif12 and myosin II. Thus, DdAurora may represent the ancestral kinase that gave rise to the different Aurora kinases in animals and also those in other organisms.
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Shin, Soon, Youngshim Lee, Beom Kim, Junho Lee, Seunghyun Ahn, Dongsoo Koh, Yoongho Lim, and Young Lee. "Inhibitory Effect of Synthetic Flavone Derivatives on Pan-Aurora Kinases: Induction of G2/M Cell-Cycle Arrest and Apoptosis in HCT116 Human Colon Cancer Cells." International Journal of Molecular Sciences 19, no. 12 (December 17, 2018): 4086. http://dx.doi.org/10.3390/ijms19124086.
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Members of the aurora kinase family are Ser/Thr kinases involved in regulating mitosis. Multiple promising clinical trials to target aurora kinases are in development. To discover flavones showing growth inhibitory effects on cancer cells, 36 flavone derivatives were prepared, and their cytotoxicity was measured using a long-term clonogenic survival assay. Their half-maximal growth inhibitory effects against HCT116 human colon cancer cells were observed at the sub-micromolar level. Pharmacophores were derived based on three-dimensional quantitative structure–activity calculations. Because plant-derived flavones inhibit aurora kinase B, we selected 5-methoxy-2-(2-methoxynaphthalen-1-yl)-4H-chromen-4-one (derivative 31), which showed the best half-maximal cell growth inhibitory effect, and tested whether it can inhibit aurora kinases in HCT116 colon cancer cells. We found that derivative 31 inhibited the phosphorylation of aurora kinases A, aurora kinases B and aurora kinases C, suggesting that derivative 31 is a potential pan-aurora kinase inhibitor. The results of our analysis of the binding modes between derivative 31 and aurora A and aurora B kinases using in-silico docking were consistent with the pharmacophores proposed in this study.
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Chen, Ya-Ping, Hui-Ju Lin, Kung-Chao Chang, Jiann-Shiuh Chen, Ming-Ying Tsai, Liang-Yi Hung, and Tsai-Yun Chen. "Targeting Aurora Kinases in Acute Lymphoblastic Leukemia." Blood 120, no. 21 (November 16, 2012): 4907. http://dx.doi.org/10.1182/blood.v120.21.4907.4907.
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Abstract Abstract 4907 Introduction: Despite improved treatment outcome in acute lymphoblastic leukemia (ALL), drug resistance and disease recurrence remain major obstacles in specific subgroups. Thus, there is an urgent need to identify new targets for therapy. Several studies showed that Aurora kinases were therapeutic targets in cancer therapy, including solid tumors and hematological malignancies. Here we describe preclinical testing of Aurora kinase inhibitors in ALL and the molecular mechanism of different drug activity. Materials and methods: Quantitative RT-PCR and Western blot were used to assess the expressions of Aurora kinases and their activators in ALL. RT-PCR was used to detect the expression of MDR-1. To test activity against Aurora kinases, different ALL cell lines were treated with various concentrations of Aurora kinase inhibitors “VE-465 and VX-680”. The effects of Aurora kinase inhibitors on the cell cycle were evaluated by flow cytometry. Gene expression profiling was performed to identify the candidate targets which regulate the different drug sensitivity. Transient knockdown and overexpression of candidate genes in ALL cell lines were also employed in this study. Results: Nine ALL cell lines treated with Aurora kinase inhibitors (VE-465 and VX-680) exhibited different drug sensitivity. Five ALL cell lines were sensitive to drug treatment with IC50 around 10–40 nM, including MLL-AF4-positive and BCR-ABL-positive cell lines. However, RPMI-8402 was one of the three cell lines which were resistant to VE-465 and VX-680 with IC50 more than 10 μM. Among these sensitive ALL cell lines, treatment of Aurora kinase inhibitors resulted in an increased G2/M and sub-G1 populations. In contrast, drug-resistant ALL cell lines showed increased polyploidy status after exposure to Aurora kinase inhibitors. The different treatment efficacy was not related to the expression of Aurora kinases, their activators or MDR-1. In order to elucidate the molecular mechanism to regulate the different drug sensitivity, microarray study was performed. It showed that treatment of Aurora kinase inhibitors resulted in differential expressions of genes (75 up-regulated and 90 down-regulated genes) and CDKN1Awas one of the potential molecules which regulated the treatment diversity. RT-PCR and Western blot confirmed the cDNA microarray data: CDKN1A was up-regulated after treatment with Aurora kinase inhibitors in the drug-sensitive cell lines, but no change in the level of CDKN1A in the drug-resistance cell lines. Knockdown of CDKN1A in drug-sensitive cell lines impaired the treatment activity. Over-expression of CDKN1A in drug-resistant cell lines increased the anti-leukemia effect of Aurora kinase inhibitors. Conclusion: These data suggest that treatment with Aurora kinase inhibitors may be a novel and effective therapy in specific subgroups of ALL, including MLL-AF4-positive ALL. These data show that status of Aurora kinases, their activators or MDR-1 does not correlate with the drug susceptibility in ALL cell lines. The susceptibility to Aurora kinase inhibitors in ALL depends on the activation status of CDKN1A. Disclosures: No relevant conflicts of interest to declare.
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Heo, Sook-Kyoung, Eui-Kyu Noh, Yoo Kyung Jeong, Lan Jeong Ju, Jun Young Sung, Ho-Min Yu, Jaekyung Cheon, et al. "Radotinib inhibits mitosis entry in acute myeloid leukemia cells via suppression of Aurora kinase A expression." Tumor Biology 41, no. 5 (May 2019): 101042831984861. http://dx.doi.org/10.1177/1010428319848612.
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Aurora kinases play critical roles in regulating several processes pivotal for mitosis. Radotinib, which is approved in South Korea as a second-line treatment for chronic myeloid leukemia, inhibits the tyrosine kinase BCR-ABL and platelet-derived growth factor receptor. However, the effects of radotinib on Aurora kinase expression in acute myeloid leukemia are not well studied. Interestingly, the cytotoxicity of acute myeloid leukemia cells was increased by radotinib treatment. Radotinib significantly decreased the expression of cyclin-dependent kinase 1 and cyclin B1, the key regulators of G2/M phase, and inhibited the expression of Aurora kinase A and Aurora kinase B in acute myeloid leukemia cells. In addition, radotinib decreased the expression and binding between p-Aurora kinase A and TPX2, which are required for spindle assembly. Furthermore, it reduced Aurora kinase A and polo-like kinase 1 phosphorylation and suppressed the expression of α-, β-, and γ-tubulin in acute myeloid leukemia cells. Furthermore, radotinib significantly suppressed the key regulators of G2/M phase including cyclin B1 and Aurora kinase A in a xenograft animal model. Therefore, our results suggest that radotinib can abrogate acute myeloid leukemia cell growth both in vitro and in vivo and may serve as a candidate agent or a chemosensitizer for treating acute myeloid leukemia.
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Crosio, Claudia, Gian Maria Fimia, Romain Loury, Masashi Kimura, Yukio Okano, Hongyi Zhou, Subrata Sen, C. David Allis, and Paolo Sassone-Corsi. "Mitotic Phosphorylation of Histone H3: Spatio-Temporal Regulation by Mammalian Aurora Kinases." Molecular and Cellular Biology 22, no. 3 (February 1, 2002): 874–85. http://dx.doi.org/10.1128/mcb.22.3.874-885.2002.
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ABSTRACT Phosphorylation at a highly conserved serine residue (Ser-10) in the histone H3 tail is considered to be a crucial event for the onset of mitosis. This modification appears early in the G2 phase within pericentromeric heterochromatin and spreads in an ordered fashion coincident with mitotic chromosome condensation. Mutation of Ser-10 is essential in Tetrahymena, since it results in abnormal chromosome segregation and extensive chromosome loss during mitosis and meiosis, establishing a strong link between signaling and chromosome dynamics. Although mitotic H3 phosphorylation has been long recognized, the transduction routes and the identity of the protein kinases involved have been elusive. Here we show that the expression of Aurora-A and Aurora-B, two kinases of the Aurora/AIK family, is tightly coordinated with H3 phosphorylation during the G2/M transition. During the G2 phase, the Aurora-A kinase is coexpressed while the Aurora-B kinase colocalizes with phosphorylated histone H3. At prophase and metaphase, Aurora-A is highly localized in the centrosomic region and in the spindle poles while Aurora-B is present in the centromeric region concurrent with H3 phosphorylation, to then translocate by cytokinesis to the midbody region. Both Aurora-A and Aurora-B proteins physically interact with the H3 tail and efficiently phosphorylate Ser10 both in vitro and in vivo, even if Aurora-A appears to be a better H3 kinase than Aurora-B. Since Aurora-A and Aurora-B are known to be overexpressed in a variety of human cancers, our findings provide an attractive link between cell transformation, chromatin modifications and a specific kinase system.
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Blengini, Cecilia S., Gyu Ik Jung, Mansour Aboelenain, and Karen Schindler. "A field guide to Aurora kinase inhibitors: an oocyte perspective." Reproduction 164, no. 4 (October 1, 2022): V5—V7. http://dx.doi.org/10.1530/rep-22-0292.
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In brief The Aurora protein kinases have critical functions in controlling oocyte meiotic maturation. In this study, we describe an assay for examining their activation state in oocytes and establish the best working doses of three commonly used inhibitors. Abstract Several small molecule inhibitors exist for targeting Aurora kinase proteins in somatic cells. From this point of view, we evaluate the specificity of these inhibitors in mouse oocytes, and we demonstrate that MLN 8237 and AZD 1152 are specific for Aurora kinase A and Aurora kinase C, respectively, only when used at low concentrations.
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DeLuca, Keith F., Amanda Meppelink, Amanda J. Broad, Jeanne E. Mick, Olve B. Peersen, Sibel Pektas, Susanne M. A. Lens, and Jennifer G. DeLuca. "Aurora A kinase phosphorylates Hec1 to regulate metaphase kinetochore–microtubule dynamics." Journal of Cell Biology 217, no. 1 (November 29, 2017): 163–77. http://dx.doi.org/10.1083/jcb.201707160.
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Precise regulation of kinetochore–microtubule attachments is essential for successful chromosome segregation. Central to this regulation is Aurora B kinase, which phosphorylates kinetochore substrates to promote microtubule turnover. A critical target of Aurora B is the N-terminal “tail” domain of Hec1, which is a component of the NDC80 complex, a force-transducing link between kinetochores and microtubules. Although Aurora B is regarded as the “master regulator” of kinetochore–microtubule attachment, other mitotic kinases likely contribute to Hec1 phosphorylation. In this study, we demonstrate that Aurora A kinase regulates kinetochore–microtubule dynamics of metaphase chromosomes, and we identify Hec1 S69, a previously uncharacterized phosphorylation target site in the Hec1 tail, as a critical Aurora A substrate for this regulation. Additionally, we demonstrate that Aurora A kinase associates with inner centromere protein (INCENP) during mitosis and that INCENP is competent to drive accumulation of the kinase to the centromere region of mitotic chromosomes. These findings reveal that both Aurora A and B contribute to kinetochore–microtubule attachment dynamics, and they uncover an unexpected role for Aurora A in late mitosis.
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Kitzen, J. J. E. M., M. J. A. de Jonge, and J. Verweij. "Aurora kinase inhibitors." Critical Reviews in Oncology/Hematology 73, no. 2 (February 2010): 99–110. http://dx.doi.org/10.1016/j.critrevonc.2009.03.009.
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Ditchfield, Claire, Victoria L. Johnson, Anthony Tighe, Rebecca Ellston, Carolyn Haworth, Trevor Johnson, Andrew Mortlock, Nicholas Keen, and Stephen S. Taylor. "Aurora B couples chromosome alignment with anaphase by targeting BubR1, Mad2, and Cenp-E to kinetochores." Journal of Cell Biology 161, no. 2 (April 28, 2003): 267–80. http://dx.doi.org/10.1083/jcb.200208091.
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The Aurora/Ipl1 family of protein kinases plays multiple roles in mitosis and cytokinesis. Here, we describe ZM447439, a novel selective Aurora kinase inhibitor. Cells treated with ZM447439 progress through interphase, enter mitosis normally, and assemble bipolar spindles. However, chromosome alignment, segregation, and cytokinesis all fail. Despite the presence of maloriented chromosomes, ZM447439-treated cells exit mitosis with normal kinetics, indicating that the spindle checkpoint is compromised. Indeed, ZM447439 prevents mitotic arrest after exposure to paclitaxel. RNA interference experiments suggest that these phenotypes are due to inhibition of Aurora B, not Aurora A or some other kinase. In the absence of Aurora B function, kinetochore localization of the spindle checkpoint components BubR1, Mad2, and Cenp-E is diminished. Furthermore, inhibition of Aurora B kinase activity prevents the rebinding of BubR1 to metaphase kinetochores after a reduction in centromeric tension. Aurora B kinase activity is also required for phosphorylation of BubR1 on entry into mitosis. Finally, we show that BubR1 is not only required for spindle checkpoint function, but is also required for chromosome alignment. Together, these results suggest that by targeting checkpoint proteins to kinetochores, Aurora B couples chromosome alignment with anaphase onset.
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Kobayashi, Miki, Satoki Nakamura, Takaaki Ono, Yuya Sugimoto, Naohi Sahara, Kaori Shinjo, Kazuyuki Shigeno, and Kazunori Ohnishi. "Analysis of Aurora Kinase Expressions and Cell Cycle Regulation by Aurora-C in Leukemia Cells." Blood 108, no. 11 (November 16, 2006): 1366. http://dx.doi.org/10.1182/blood.v108.11.1366.1366.
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Abstract Background: The conserved Aurora family kinases, a family of mitotic serine/threonine kinases, have three members (Aurora-A, -B and -C) in mammalian cells. The Aurora kinases are involved in the regulation of cell cycle progression, and alterations in their expression have been shown to associate with cell malignant transformation. Aurora A localizes to the centrosomes during anaphase, and it is required for mitotic entry. Aurora B regulates the formation of a stable bipolar spindle-kinetochore attachment in mitosis. The function of Aurora-C in mammalian cells has not been studied extensively. In this study, we investigated that human leukemia cells expressed all 3 Aurora kinases at both protein and mRNA level, and the mechanisms of cell cycle regulation by knock down of Aurora C in leukemia cells. Methods: In this study, we used the 7 human leukemia cell lines, K562, NB4, HL60, U937, CEM, MOLT4, SUP-B15 cells. The expression levels of mRNA and proteins of Aurora kinases were evaluated by RT-PCR and western blot. The analysis of proliferation and cell cycle were performed by MTT assay and FCM, respectively. Results: The mRNA of Aurora-A and Aurora-B are highly expressed in human leukemia cell lines (K562, NB4, HL60, U937, CEM, MOLT4, SUP-B15 cells), while the mRNA of Aurora C is not only expressed highly in all cells. In contrast, an increase in the protein level of the 3 kinases was found in all cell lines. These observations suggested posttranscriptional mechanisms, which modulate the expression of Aurora C. In cell cycle analysis by flow cytometory, the knock down of Aurora C by siRNA induced G0/G1 arrest and apoptosis in leukemia cells, and increased the protein levels of p27Kip1 and decreased Skp2 by western blot. In MTT assay, it was revealed that the growth inhibition of leukemia cells transfected with siRNA Aurora C compared with leukemia cells untransfected with siRNA Aurora C. Moreover, We showed that Aurora C was associated with Survivin and directly bound to Survivin by immunoprecipitation and western blot. Conclusion: We found that human leukemia cells expressed all 3 members of the Aurora kinase family. These results suggest that the Aurora kinases may play a relevant role in leukemia cells. Among these Aurora kinases, Aurora C interacted with Survivin and prevented apoptosis of leukemia cells, and induced cell cycle progression. Our results showed that Aurora-C may serve as a key regulator in cell division and survival. These results suggest that the Aurora C kinase may play an important role in leukemia cells, and may represent a target for leukemia therapy.
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Seitz, Anna Katharina, Nikolas von Bubnoff, Samantha M. Sarno, Christian Peschel, and Justus Duyster. "Activity of Serono-AS703569, a Dual Inhibitor of Bcr-Abl and Aurora Kinases in Bcr-Abl Transformed Cells, Is Dependent On Aurora B Inhibition, and Is Not Affected by the Presence of the Highly Imatinib Resistant Bcr-Abl Mutation T315I." Blood 114, no. 22 (November 20, 2009): 3247. http://dx.doi.org/10.1182/blood.v114.22.3247.3247.
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Abstract Abstract 3247 Poster Board III-1 The tyrosine kinase inhibitor Imatinib is the gold standard in conventional treatment of CML. However, the emergence of resistance to IM remains a major problem. Alternative therapeutic strategies of IM-resistant BCR-ABL positive leukemias are urgently needed. One promising target for anticancer therapeutics is represented by the Aurora kinase family. These serine/threonine kinases are involved in regulating multiple steps of mitosis, including formation of bipolar spindle, chromosome alignment, spindle checkpoint function and cytokinesis. We report on studies accomplished with a small molecule inhibitor AS703569 (Merck Serono), which targets Bcr-Abl and Aurora kinases A-C. We could show that AS703569 exhibited strong anti-proliferative and pro-apoptotic activity against murine BaF3- cells ectopically expressing wild type (wt) or IM-resistant BCR-ABL mutants, including those harbouring the strongly resistant T315I mutation. This effect was observed already at rather low-AS703569 concentrations, at which Aurora- but not the Bcr-Abl kinase was inhibited. Furthermore, in cell cycle analysis we observed cells with a large 4N peak and DNA content more than 4N, indicating extensive polyploidisation, a consequence of continued cell cycle progression in the absence of cell division. Recent studies have revealed that this phenotype is based on suppression of Aurora B kinase activity, indicating that Aurora B inhibition is the major effect of AS703569 in Bcr-Abl positive cells. To confirm this assumption we designed MSCV based retroviruses encoding different point mutations in the Aurora B ATP binding site, which should lead to resistance against AS703569. By this strategy we were able to identify an AS703569 resistant mutant (Aurora B G216V). This mutant shows significant resistance in vitro and is able to augment the antiproliferative capacity of AS703569 in Bcr-Abl positive cells. Taken together, our data demonstrate that anti-proliferative effects of AS703569 in Bcr-Abl positive cells are primarily mediated by functional inhibition of Aurora kinases, especially of Aurora kinase B. Since Aurora kinases are clearly implicated in tumorgenesis, they will become a high potential therapeutic target for anticancer therapy. Disclosures: No relevant conflicts of interest to declare.
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Lake, Eric W., Joseph M. Muretta, Andrew R. Thompson, Damien M. Rasmussen, Abir Majumdar, Erik B. Faber, Emily F. Ruff, David D. Thomas, and Nicholas M. Levinson. "Quantitative conformational profiling of kinase inhibitors reveals origins of selectivity for Aurora kinase activation states." Proceedings of the National Academy of Sciences 115, no. 51 (December 5, 2018): E11894—E11903. http://dx.doi.org/10.1073/pnas.1811158115.
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Protein kinases undergo large-scale structural changes that tightly regulate function and control recognition by small-molecule inhibitors. Methods for quantifying the conformational effects of inhibitors and linking them to an understanding of selectivity patterns have long been elusive. We have developed an ultrafast time-resolved fluorescence methodology that tracks structural movements of the kinase activation loop in solution with angstrom-level precision, and can resolve multiple structural states and quantify conformational shifts between states. Profiling a panel of clinically relevant Aurora kinase inhibitors against the mitotic kinase Aurora A revealed a wide range of conformational preferences, with all inhibitors promoting either the active DFG-in state or the inactive DFG-out state, but to widely differing extents. Remarkably, these conformational preferences explain broad patterns of inhibitor selectivity across different activation states of Aurora A, with DFG-out inhibitors preferentially binding Aurora A activated by phosphorylation on the activation loop, which dynamically samples the DFG-out state, and DFG-in inhibitors binding preferentially to Aurora A constrained in the DFG-in state by its allosteric activator Tpx2. The results suggest that many inhibitors currently in clinical development may be capable of differentiating between Aurora A signaling pathways implicated in normal mitotic control and in melanoma, neuroblastoma, and prostate cancer. The technology is applicable to a wide range of clinically important kinases and could provide a wealth of valuable structure–activity information for the development of inhibitors that exploit differences in conformational dynamics to achieve enhanced selectivity.
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Lim, Daniel C., Vladimir Joukov, T. Justin Rettenmaier, Akiko Kumagai, William G. Dunphy, James A. Wells, and Michael B. Yaffe. "Redox priming promotes Aurora A activation during mitosis." Science Signaling 13, no. 641 (July 21, 2020): eabb6707. http://dx.doi.org/10.1126/scisignal.abb6707.
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Cell cycle–dependent redox changes can mediate transient covalent modifications of cysteine thiols to modulate the activities of regulatory kinases and phosphatases. Our previously reported finding that protein cysteine oxidation is increased during mitosis relative to other cell cycle phases suggests that redox modifications could play prominent roles in regulating mitotic processes. The Aurora family of kinases and their downstream targets are key components of the cellular machinery that ensures the proper execution of mitosis and the accurate segregation of chromosomes to daughter cells. In this study, x-ray crystal structures of the Aurora A kinase domain delineate redox-sensitive cysteine residues that, upon covalent modification, can allosterically regulate kinase activity and oligomerization state. We showed in both Xenopus laevis egg extracts and mammalian cells that a conserved cysteine residue within the Aurora A activation loop is crucial for Aurora A activation by autophosphorylation. We further showed that covalent disulfide adducts of this residue promote autophosphorylation of the Aurora A kinase domain. These findings reveal a potential mechanistic link between Aurora A activation and changes in the intracellular redox state during mitosis and provide insights into how novel small-molecule inhibitors may be developed to target specific subpopulations of Aurora A.
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Mahadevan, Daruka, Wenqing Qi, Laurence Cooke, Xiabing Lui, Daniel Oscar Persky, Lisa M. Rimsza, and Thomas P. Miller. "Targeting Aurora Kinase in Aggressive B-Cell Non-Hodgkin's Lymphomas." Blood 114, no. 22 (November 20, 2009): 284. http://dx.doi.org/10.1182/blood.v114.22.284.284.
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Abstract Abstract 284 Aurora kinases (A and B) are oncogenic serine/threonine (S/T) kinases that play central roles in the mitotic phase of the eukaryotic cell cycle. Over-expression of Aurora kinases during the cell cycle over-rides mitotic and spindle check points leading to aneuploidy in many human cancers; Aurora kinases are therefore attractive therapeutic targets. Gene expression profiling in aggressive B- and T-cell non-Hodgkin's lymphoma (NHL) has shown the Aurora kinases to be over-expressed and they may be key component genes of the ‘proliferative' signature. We hypothesized (1) Aurora kinases are over-expressed in human aggressive B-cell NHL (mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL) and transformed follicular lymphoma (TFL)), (2) Aurora ATP-binding site small molecule inhibitor (SMI) is effective in promoting apoptosis in cell culture and tumor growth inhibition (TGI) in mouse xenograft model(s) of NHL, and (3) Aurora SMI will be safe and effective in treating patients with relapsed aggressive B-cell NHL in early phase clinical trials. To analyze Aurora expression, tissue microarrays (TMA) were constructed from 43 patients with DLBCL and 40 with MCL, and Aurora A and B expression optimized with commercially available antibodies by immunohistochemistry (IHC). The IHC was rated as a staining intensity on a scale of 0 to 3+. The NHL TMAs demonstrated intense staining (2+ to 3+) for Aurora A (nucleus) and Aurora B (nucleus) in >60% compared to normal lymph nodes. We also analyzed the Lymphoma/Leukemia Molecular Profiling Project (LLMPP) publicly available database for Aurora A and B expression in MCL and found a worse survival in those with A > B over-expression (p<0.01). Since both Auroras are transforming genes, the LLMPP data support the conclusion that these S/T kinases are associated with a poor prognosis and are potential targets for therapy. Western blotting analysis of 13 B-cell NHL cell lines (DLBCL, MCL and TFL) for Aurora A and B expression showed significant over-expression compared to B-cells isolated from normal lymph nodes. Aurora A knockdown by shRNA in the B-NHL cell lines showed inhibition of mitosis with a polyploid phenotype (4n, 8n) that ends in apoptosis as shown by PARP-cleavage. The Aurora A specific inhibitor (MLN8237) evaluated in the 13 NHL cell lines phenocopies shRNA knockdown with associated inhibition of proliferation (IC50=0.05 mM) and promotes apoptosis (flow cytometry, PARP-cleavage) in a dose-dependent manner. Combination of MLN8237 with a microtubule targeting agent (docetaxel) to abrogate the spindle checkpoint is synergistic in a sequence specific manner. Moreover, MLN8237 effectively inhibits Aurora A auto-phosphorylation and eliminates phospho-histone H3 (Ser10) phosphorylation. Currently, 2 mouse MCL (Granta 519) xenograft models are underway evaluating tumor growth inhibition (TGI), safety and survival of MLN8237 alone and in combination with docetaxel or rituximab respectively. Preliminary data show that MLN8237 is synergistic with docetaxel in TGI in the MCL xenograft model. Together the data suggest inhibition of Aurora kinases may offer a promising treatment strategy for patients with aggressive B-cell NHL [Funded by the Lymphoma SPORE, P50 CA130805501A1, PI: Richard Fisher, MD.]. Disclosures: Rimsza: High Throughput Genomics:.
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Zeng, Kang, Ricardo Nunes Bastos, Francis A. Barr, and Ulrike Gruneberg. "Protein phosphatase 6 regulates mitotic spindle formation by controlling the T-loop phosphorylation state of Aurora A bound to its activator TPX2." Journal of Cell Biology 191, no. 7 (December 27, 2010): 1315–32. http://dx.doi.org/10.1083/jcb.201008106.
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Many protein kinases are activated by a conserved regulatory step involving T-loop phosphorylation. Although there is considerable focus on kinase activator proteins, the importance of specific T-loop phosphatases reversing kinase activation has been underappreciated. We find that the protein phosphatase 6 (PP6) holoenzyme is the major T-loop phosphatase for Aurora A, an essential mitotic kinase. Loss of PP6 function by depletion of catalytic or regulatory subunits interferes with spindle formation and chromosome alignment because of increased Aurora A activity. Aurora A T-loop phosphorylation and the stability of the Aurora A–TPX2 complex are increased in cells depleted of PP6 but not other phosphatases. Furthermore, purified PP6 acts as a T-loop phosphatase for Aurora A–TPX2 complexes in vitro, whereas catalytically inactive mutants cannot dephosphorylate Aurora A or rescue the PPP6C depletion phenotype. These results demonstrate a hitherto unappreciated role for PP6 as the T-loop phosphatase regulating Aurora A activity during spindle formation and suggest the general importance of this form of regulation.
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Slatter, Andrew F., Spencer Campbell, and Richard M. Angell. "Development of a Fluorescence Intensity Assay for the Mitotic Serine/Threonine Protein Kinase Aurora-A." Journal of Biomolecular Screening 18, no. 2 (September 14, 2012): 219–25. http://dx.doi.org/10.1177/1087057112459888.
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The Aurora kinases are a group of serine/threonine protein kinases that regulate key steps during mitosis, and deregulation of these proteins (e.g., by gene amplification or overexpression) has been linked to a wide variety of tumor types. Thus, Aurora-A and Aurora-B have been intensely studied as targets for anticancer therapy and are now clinically validated targets. Here we report on the development of a novel fluorescence intensity binding assay for Aurora-A kinase inhibitors using a fluorescently labeled probe compound that shows intramolecular quenching when unbound but exhibits a dramatic increase in fluorescence when bound to Aurora-A.
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Santo, Loredana, Teru Hideshima, Erik A. Nelson, Diana Cirstea, Madhavi Bandi, Hiroshi Ikeda, Gullu Gorgun, et al. "AT9283, a Small Molecule Multi-Targeted Kinase Inhibitor Induces Antimyeloma Activity Via Potent Aurora Kinase and STAT3 Inhibition." Blood 114, no. 22 (November 20, 2009): 3833. http://dx.doi.org/10.1182/blood.v114.22.3833.3833.
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Abstract Abstract 3833 Poster Board III-769 Aurora kinases, a family of mitotic regulators, whose expression has been recently linked to genetic instability and cellular proliferation in several cancers including multiple myeloma (MM), are being studied as novel mitotic therapeutic targets. Aurora A plays a crucial role in centrosome separation and spindle assembly and is required for mitosis and bipolar mitotic spindle formation. Aurora B, a member of the chromosomal passenger complex, is required for chromosome segregation, spindle assembly checkpoint and cytokinesis. Both aurora kinase A and B are significantly overexpressed in MM cells prompting the investigation of aurora kinase inhibitors as a therapeutic strategy in MM. Here, we investigated the preclinical activity of a small molecule multi-targeted inhibitor, AT9283, with potent in vitro kinase activity against aurora A and B kinases (3 nM), JAK2 and 3 (at 1.2 and 1.1 nM, respectively) and Abl T315I (at 4 nM). Growth inhibitory effects of AT9283 on MM cell lines and patient derived cells was observed with IC50 values of 0.25μM -0.5 μM at 48 hours using a [3H]-thymidine incorporation assay. Cell cycle analysis following AT9283 treatment resulted in increased G2/M phase and polyploidy consistent with failed cytokinesis (associated with aurora kinase B inhibition) confirmed by immunofluorescence assay. This was followed by induction of apoptosis assessed by Annexin V+PI+ staining peaking at 48 - 72 hours with associated caspase-8/-9 cleavage. The cellular inhibition of aurora kinase activity by AT9283 was confirmed by evaluating the phosphorylation of histone H3 at serine-10, a direct downstream substrate of aurora B kinase. Pretreatment of MM.1S cells with nocodazole, known to induce maximal phosphorylation of histone H3 by causing an M-phase block, resulted in decreased levels of phosphorylated histone H3 after AT9283 treatment suggesting the role of aurora B kinase inhibition by AT9283. Importantly, in addition to aurora kinase inhibition, we observed that AT9283 also inhibited signal transducer and activator of transcription (STAT3) tyrosine phosphorylation in MM cells within 30 minutes of treatment. Janus Kinase (JAK)2/STAT3 pathway is one of the major signaling cascades activated by gp130 family member cytokines that promotes MM cell survival. The effect of AT9283 on pSTAT3 inhibition was further investigated by using U3A cells stably expressing a luciferase reporter gene under the control of a STAT-dependent promoter. AT9283 inhibited STAT3-dependent luciferase activity with an EC50 of approximately 0.125 μM suggesting that STAT3 was functionally inhibited by AT9283. Since MM cell lines with the constitutive STAT3 tyrosine phosphorylation were more sensitive to AT9283, ongoing studies are aimed at understanding whether AT9283-induced effects on the JAK/STAT pathway enhances the efficacy of the aurora kinase inhibition in the context of MM. Finally, in vivo data using a xenograft mouse model of human MM show that mice treated with AT9283 demonstrated slower tumor growth compared to the control group without adverse effects. Our results show pleiotropic effects of AT9283 in MM and warrant further study to determine its suitability for clinical evaluation in MM. Disclosures: Squires: Astex Therapeutics, Ldt: Employment. Yule:Astex Therapeutics Ldt: Employment. Anderson:Novartis, Millennium, Celgene: Consultancy, Honoraria, Research Funding. Raje:Celgene, Norvartis, Astrazeneca: Research Funding.
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Reiman, Tony, Robert P. Evans, Claudia Naber, Tara Steffler, Jonathan J. Keats, Troy Perry, Christopher A. Maxwell, Heidi Chau, Andrew R. Belch, and Linda M. Pilarski. "Aurora Kinases as Therapeutic Targets in Multiple Myeloma." Blood 108, no. 11 (November 16, 2006): 847. http://dx.doi.org/10.1182/blood.v108.11.847.847.
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Abstract BACKGROUND: We have previously found that in multiple myeloma there is amplification of the centrosome, the organelle that nucleates the mitotic spindle. We have reported that RHAMM is a component of the centrosome which interacts with TPX2, the protein that targets Aurora A kinase to the mitotic spindle. We have also shown that RHAMM expression and alternative splicing in myeloma correlate with centrosome amplification, aggressive disease and poor survival. These findings led us to speculate that Aurora A and possibly other Aurora kinases are potential therapeutic targets in myeloma. METHODS: We examined the expression of Aurora A, B and C kinases in 5 myeloma cell lines and autoMACS-purified CD138+ myeloma bone marrow plasma cells from 20 patients. We assessed the anti-proliferative and pro-apoptotic effects of Aurora A knockdown in myeloma cell lines with RNA interference. We investigated the anti-myeloma activity of two potent, selective Aurora kinase inhibitors, VE-465 (Merck/Vertex) and AZD1152 (AstraZeneca), in 5 myeloma cell lines, in CD138+ bone marrow plasma cells from 2 myeloma patients, and in a NOD/SCID murine xenograft model. RESULTS: Aurora A, B and C kinases are ubiquitously expressed in both myeloma cell lines and myeloma bone marrow plasma cells. Expression levels vary among patients. Aurora A and B are expressed in myeloma plasma cells at levels comparable to that seen in the CD138- cells from the same marrow sample, and comparable to the levels seen in normal marrow from control individuals. Aurora C, while expressed at low levels, is consistently ectopically overexpressed in myeloma plasma cells relative to coexisting CD138- cells and normal marrow. In myeloma cell lines, Aurora A knockdown with RNA interference induces apoptosis and cell killing. In all five myeloma cell lines tested, and in myeloma bone marrow plasma cells from two patients, both VE-465 and AZD1152 induce apoptosis and myeloma cell killing at nanomolar concentrations, to varying degrees (20–80% reduction in cell viability). VE-465 is known to inhibit all three Aurora kinases with comparable specificity, while AZD1152 is known to inhibit Aurora B and C more selectively than Aurora A. Despite these differences in activity, both compounds have comparable pre-clinical efficacy against myeloma. Myeloma cell lines treated with either agent demonstrate a phenotype consistent with target inhibition. Both drugs show additive effects on killing of cell lines and primary myeloma cells when combined with dexamethasone, even in dexamethasone-resistant cells. Anti-myeloma activity was seen with single agent Aurora kinase inhibition in the murine model, at well tolerated doses. CONCLUSIONS: Aurora kinases are potential therapeutic targets in myeloma. Aurora kinase inhibitors comprise an emerging class of anti-cancer drug therapy that deserves further evaluation for myeloma patients.
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Kojima, Kensuke, Marina Konopleva, Twee Tsao, Hideki Nakakuma, and Michael Andreeff. "Concomitant inhibition of Mdm2-p53 interaction and Aurora kinases activates the p53-dependent postmitotic checkpoints and synergistically induces p53-mediated mitochondrial apoptosis along with reduced endoreduplication in acute myelogenous leukemia." Blood 112, no. 7 (October 1, 2008): 2886–95. http://dx.doi.org/10.1182/blood-2008-01-128611.
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Abstract Aberrant expression of Aurora kinases and inactivation of wild-type p53 by Mdm2 overexpression are frequent molecular events in acute myelogenous leukemia (AML), and preclinical data for inhibition of Aurora kinases or Mdm2 are promising. However, it remains largely unknown whether the viability of cells exposed to Aurora kinase inhibitors depends on the p53 status. We investigated the interaction of Aurora kinases and p53 pathways after their simultaneous blockades using a small-molecule pan-Aurora kinase inhibitor, MK-0457, and a selective small-molecule antagonist of Mdm2, Nutlin-3. We found that MK-0457, which itself activates p53 signaling, acts synergistically with Nutlin-3 to induce apoptosis in wild-type p53 AML cell lines OCI-AML-3 and MOLM-13 but not in p53-null HL-60 cells. MK-0457 and Nutlin-3 showed synergism in inducing p53, conformational change of Bax and Δψm loss, suggesting an involvement of p53-mediated mitochondrial apoptosis. Nutlin-3 constrained endoreduplication after Aurora inhibition via activation of a p53-dependent postmitotic checkpoint and p21 induction in pseudo-G1 cells. Our findings provide the molecular rationale for concomitant targeting of Aurora kinases and Mdm2 in AML where TP53 mutations are rare and downstream p53 signaling is mostly intact.
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Mattei, Jean Camille, Corinne Bouvier-Labit, Doriane Barets, Nicolas Macagno, Mathieu Chocry, Frédéric Chibon, Philippe Morando, et al. "Pan Aurora Kinase Inhibitor: A Promising Targeted-Therapy in Dedifferentiated Liposarcomas With Differential Efficiency Depending on Sarcoma Molecular Profile." Cancers 12, no. 3 (March 3, 2020): 583. http://dx.doi.org/10.3390/cancers12030583.
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Soft tissue sarcoma (STS) are rare and aggressive tumours. Their classification includes numerous histological subtypes of frequent poor prognosis. Liposarcomas (LPS) are the most frequent type among them, and the aggressiveness and deep localization of dedifferentiated LPS are linked to high levels of recurrence. Current treatments available today lead to five-year overall survival has remained stuck around 60–70% for the past three decades. Here, we highlight a correlation between Aurora kinasa A (AURKA) and AURKB mRNA overexpression and a low metastasis-free survival. AURKA and AURKB expression analysis at genomic and protein level on a 9-STS cell lines panel highlighted STS heterogeneity, especially in LPS subtype. AURKA and AURKB inhibition by RNAi and drug targeting with AMG 900, a pan Aurora Kinase inhibitor, in four LPS cell lines reduces cell survival and clonogenic proliferation, inducing apoptosis and polyploidy. When combined with doxorubicin, the standard treatment in STS, aurora kinases inhibitor can be considered as an enhancer of standard treatment or as an independent drug. Kinome analysis suggested its effect was linked to the inhibition of the MAP-kinase pathway, with differential drug resistance profiles depending on molecular characteristics of the tumor. Aurora Kinase inhibition by AMG 900 could be a promising therapy in STS.
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Gavriilidis, Paschalis, Alexandros Giakoustidis, and Dimitrios Giakoustidis. "Aurora Kinases and Potential Medical Applications of Aurora Kinase Inhibitors: A Review." Journal of Clinical Medicine Research 7, no. 10 (2015): 742–51. http://dx.doi.org/10.14740/jocmr2295w.
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Geddis, Amy E., and Kenneth Kaushansky. "Megakaryocytes express functional Aurora-B kinase in endomitosis." Blood 104, no. 4 (August 15, 2004): 1017–24. http://dx.doi.org/10.1182/blood-2004-02-0419.
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AbstractEndomitosis (EnM) in megakaryocytes (MKs) is characterized by abortion of mitosis in late anaphase and failure of cytokinesis; subsequent reinitiation of DNA synthesis results in polyploidy. Ablation of chromosomal passenger proteins including Aurora-B kinase causes defects in late anaphase and cytokinesis in diploid cells; thus one hypothesis is that the expression or function of these proteins in polyploid MKs is abnormal. It has been reported that Aurora-B kinase mRNA is decreased in polyploid megakaryocytic cells, suggesting that deficiency of Aurora-B kinase is responsible for EnM. We examined the localization of Aurora-B kinase and additional members of the chromosomal passenger protein and aurora kinase families in MKs. We found that in EnM MKs (1) Aurora-B kinase is present and appropriately localized to centromeres in early EnM; (2) in low-ploidy human MKs, centromeric localization of survivin and inner centromere protein (INCENP) can also be demonstrated; (3) the function of Aurora-B kinase, as measured by Ser10 phosphorylation of histone H3, is intact; and (4) aurora-A kinase localizes appropriately to centrosomes in EnM. These results suggest that EnM MKs appropriately express functional Aurora-B kinase and related proteins in early anaphase, making a simple deficiency of this protein an unlikely explanation for polyploidy in this cell type.
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Hoellein, Alexander, Stephanie Schoeffmann, Fallahi Mohammad, John L. Cleveland, Johannes Gloeckner, Marius Ueffing, Martina Rudelius, Christian Peschel, and Ulrich Keller. "Myc Commands an Aurora Kinase – Sumoylation Circuit Required for B Cell Lymphoma Growth and Survival." Blood 124, no. 21 (December 6, 2014): 3107. http://dx.doi.org/10.1182/blood.v124.21.3107.3107.
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Abstract Myc oncoproteins (c-Myc, N-Myc and L-Myc) are transcription factors that regulate cell growth, cell division and metabolism under physiologic conditions. Myc overexpression is a hallmark of Burkitt lymphoma (BL) harboring MYC/IG translocations, and is frequently present in many advanced cancers. Myc overexpression is associated with aggressive disease, which is in part due to the destruction of select targets by the ubiquitin-proteasome system, for example Skp2SCF-directed destruction of the Cdk inhibitior p27Kip1 (Keller et al., EMBO 2007, Old et al., Mol. Canc. Res. 2010). We have identified a related means of post-translational protein modification, SUMOylation, as a pathway activated by Myc. Consequently, Myc-driven human BL and manifest Eµ-Myc mouse lymphomas are characterized by a hyperSUMOylation phenotype. Targeting SUMOylation in such lymphomas by a genetic approach results in growth inhibition and blocks lymphoma maintenance in vitro and in vivo. We further found that the SUMO pathway is in particular required for intact transitioning of the G2-M cell cycle checkpoint and through mitosis. The use of pharmacologic SUMOylation inhibitors (SUMOi) accordingly resulted in cell cycle arrest, polyploidy and cell death (Hoellein et al., Blood 2014). In this current report we aimed to identify crucial players of the Myc-SUMOylation axis by applying a mass spectrometry approach that used purified SUMOylated proteins in a conditional Myc-inducible B cell model. Stable isotope labeling permitted quantitative analysis of protein SUMOylation in the Myc-on versus Myc-off state. This screen identified Aurora kinase A as a Myc-regulated target of SUMOylation. Aurora kinases are essential regulators of mitosis and cytokinesis that are indispensable for Myc-driven transformed cells, and inhibition of Aurora kinase function results in similar effects as blocking SUMOylation, namely G2-M arrest, impaired cytokinesis resulting in polyploidy, and apoptosis (den Hollander et al., Blood 2010). We confirmed Myc-specific SUMO modification of Aurora kinase A and B and found reduced SUMOylation of both kinases upon treatment with pharmacologic SUMOylation inhibitors or shRNA targeting the key SUMOylation enzymes. Overexpression of Aurora kinase A and B mutants harboring a mutated SUMOylation motif resulted in a phenotype reminiscent of pharmacological SUMOi. This phenotype is independent of the Aurora kinase function since the SUMO motif mutation does not impair kinase activity. Moreover, in a comprehensive screen for specific E3-ligases that regulate the SUMO modification of the Aurora kinases we identified several SUMO E3 ligases that are also Myc induced. In summary, we propose a Myc-Aurora-kinase-SUMOylation circuit where Myc activation allows the induction of Aurora kinase transcription as well as the transcription of critical SUMOylation pathway genes. This mechanism contributes to sufficient Aurora kinase SUMOylation allowing faithful cell cycle passage and cytokinesis. In lymphoma and possibly other Myc-dependent cancers this pathway represents a target for synthetic lethal drug applications. Disclosures No relevant conflicts of interest to declare.
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Giet, Régis, and David M. Glover. "Drosophila Aurora B Kinase Is Required for Histone H3 Phosphorylation and Condensin Recruitment during Chromosome Condensation and to Organize the Central Spindle during Cytokinesis." Journal of Cell Biology 152, no. 4 (February 12, 2001): 669–82. http://dx.doi.org/10.1083/jcb.152.4.669.
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Aurora/Ipl1-related kinases are a conserved family of enzymes that have multiple functions during mitotic progression. Although it has been possible to use conventional genetic analysis to dissect the function of aurora, the founding family member in Drosophila (Glover, D.M., M.H. Leibowitz, D.A. McLean, and H. Parry. 1995. Cell. 81:95–105), the lack of mutations in a second aurora-like kinase gene, aurora B, precluded this approach. We now show that depleting Aurora B kinase using double-stranded RNA interference in cultured Drosophila cells results in polyploidy. aurora B encodes a passenger protein that associates first with condensing chromatin, concentrates at centromeres, and then relocates onto the central spindle at anaphase. Cells depleted of the Aurora B kinase show only partial chromosome condensation at mitosis. This is associated with a reduction in levels of the serine 10 phosphorylated form of histone H3 and a failure to recruit the Barren condensin protein onto chromosomes. These defects are associated with abnormal segregation resulting from lagging chromatids and extensive chromatin bridging at anaphase, similar to the phenotype of barren mutants (Bhat, M.A., A.V. Philp, D.M. Glover, and H.J. Bellen. 1996. Cell. 87:1103–1114.). The majority of treated cells also fail to undertake cytokinesis and show a reduced density of microtubules in the central region of the spindle. This is accompanied by a failure to correctly localize the Pavarotti kinesin-like protein, essential for this process. We discuss these conserved functions of Aurora B kinase in chromosome transmission and cytokinesis.
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Verma, Anupam, J. Kimble Frazer, Alesia Trakhimets, William Heaton, Jared Bearrs, Steven Warner, David Bearrs, and Sunil Sharma. "A Novel Dual AXL/Mertk and Aurora Kinase Inhibitor Active Against T Cell Acute Lymphoblastic Leukemia." Blood 118, no. 21 (November 18, 2011): 1519. http://dx.doi.org/10.1182/blood.v118.21.1519.1519.
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Abstract Abstract 1519 INTRODUCTION: Receptor tyrosine kinases AXL and MER belong to the TYRO3 kinase family, first identified as a transforming gene in chronic myeloid leukemia and are found at high levels in various cancers, including hematopoietic malignancies like T cell acute lymphoblastic leukemia (T-ALL). Aurora kinases play important roles in chromosome alignment and cytokinesis during mitosis and are also aberrantly expressed in ALL. We describe here characterization and pre-clinical testing of Huntsman Cancer Institute-2084 (HCI-2084), a small molecule inhibitor of AXL and MER kinases that also has activity against Aurora Kinases A and B, as a novel therapeutic for T-ALL treatment, a leukemia with poor prognosis. METHODS: Quantitative RT-PCR and Western Blot confirmed elevated levels of AXL/MER expression in Jurkat, a human T-ALL, cell line. Our compound, HCI-2084, was developed using a computational structure-based approach against AXL kinase. HCI-2084 activity against AXL/MER, in cell-based assays was evaluated utilizing ATPlite. To test activity against Aurora kinase, Jurkat cells were treated with various concentrations of HCI-2084 and VX 680, a known aurora kinase inhibitor, for 24 hours. Cell lysates were evaluated for phospho-AKT (Ser473), phospho-Aurora (Thr288) and phospho-Histone H3 (Ser10) using the Meso Scale Discovery platform (MSD). Cell cycle analysis was performed on Jurkat cells incubated in the absence (negative control) or presence of 100nM HCI-2084 or VX-680 for 24 hours, stained with propidium iodide and analyzed by flow cytometry on FACS Calibur. Immunostaining was performed to evaluate the levels of phospho-Histone H3 (Ser10) and phospho-Aurora (Thr288) during mitosis in Jurkat cells incubated in the absence (negative control) or presence of 100nM HCI-2084 and VX-680 for 24 hours. In addition to the anti-phospho-Histone H3 and anti-phospho-Aurora antibodies, anti-alpha-tubulin and DAPI were used to determine the presence of mitotic chromosomes. To examine HCI-2084 as a therapeutic agent for T-ALL treatment in vivo, we tested it using transgenic Zebrafish (Danio rerio) with T-ALL driven by human MYC (hMYC). Over-expression of endogenous D. rerio axl /mertk transcripts in T-ALL from hMYC fish were verified by qRT-PCR. Fish were treated with HCI-2084, Dexamethasone (a known T-ALL therapeutic; positive control), and DMSO vehicle (HCI-2084 is reconstituted in DMSO; negative control). Trials were conducted by housing fish with fluorescently-labeled T-ALL (GFP-tagged) in water containing the agent being tested, for 14 days with monitoring of disease response by fluorescent microscopy. RESULTS: In in vitro studies, HCI-2084 showed potent activity in cell viability assays with an IC50 of 12 nM against AXL, 60 nM against MERTK and 15 nM against Aurora kinase. MSD assays demonstrated efficacy at 1 uM for reduction of phospho-AKT, phospho-Histone H3 and phospho-Aurora, as seen with VX 680. Cell cycle analyses performed on HCI-2084-treated Jurkat cells showed a significantly increased G2/M population and an accumulation of cells with ≥4N DNA, indicative of Aurora B inhibition and endo-reduplication (Figure A & B). Immunofluorescence analyzed using fluorescent microscopy demonstrated mitotic arrest with loss of phospho-Histone H3 and phospho-Aurora staining, demonstrating inhibition of Aurora kinase activity. HCI-2084 was also a potent therapeutic against Zebrafish T-ALL. Fish treated at 1uM HCI-2084 for 14 days, showed complete responses (CR), with efficacy comparable to our dexamethasone positive control (Figure C). Following treatment, fish remained disease-free for several days, and overall survival was prolonged significantly relative to untreated controls. CONCLUSION: HCI-2084 shows dual action in vitro against Jurkat cells with potent cytotoxicity via AXL/MER kinase inhibition and anti-proliferative activity via Aurora kinase inhibition. In vivo, HCI-2084 demonstrates activity against a MYC-driven vertebrate model of T-ALL, prolongs survival, and is well tolerated. We conclude that HCI-2084 is a potent dual AXL/MER kinase and Aurora kinase inhibitor which should be explored further as a potential novel therapeutic in the treatment of human T-ALL. Disclosures: Sharma: Millenium: Research Funding.
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Pandya, Pujan N., Archana U. Mankad, Rakesh M. Rawal, and Kumar S. Prasanth. "Screening of diverse phytochemicals with Aurora Kinase C protein: An In Silico approach." Journal of Drug Delivery and Therapeutics 9, no. 1-s (February 15, 2019): 67–74. http://dx.doi.org/10.22270/jddt.v9i1-s.2249.
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Aurora Kinase C, a vital serine-threonine protein Kinase, is an important member of the Aurora Kinase protein family which plays an important role in mitosis is a part of Chromosomal Passenger Complex (CPC). Aurora Kinase C over expression is found to be linked with several cancer cell lines which demonstrate its oncogenic involvement and activity. Aurora C over expression in certain cancer types makes it an important target to be considered for cancer therapeutics. The present research work focuses on the Aurora Kinase C as an important target for computational studies. The protein model of Aurora Kinase C, as a proten target on docking with 1500 natural compounds (phytochemicals) reveals the binding of the natural ligand 3-beta,23,28-trihydroxy-12-oleanene 23-caffeate belonging to the terpenoid class with highest docking score. This best bound ligand with the protein Aurora Kinase C was chosen for further understanding their protein-ligand interactions at the the molecular level using the molecular dynamic simulation approach. Stability of the protein-ligand complex and its conformation helps in disclosing the potentiality of the best bound ligand to be further chosen as an important small molecule inhibitor that would help playing a lead role in further drug discovery process
Keywords: Aurora Kinase C, Cancer, Phytochemicals, Docking, Molecular Dynamics
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Karatas, Mehmet, Apirat Chaikuad, Bianca Berger, Michael H. G. Kubbutat, Frank Totzke, Stefan Knapp, and Conrad Kunick. "7-(2-Anilinopyrimidin-4-yl)-1-benzazepin-2-ones Designed by a “Cut and Glue” Strategy Are Dual Aurora A/VEGF-R Kinase Inhibitors." Molecules 26, no. 6 (March 14, 2021): 1611. http://dx.doi.org/10.3390/molecules26061611.
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Although overexpression and hyperactivity of protein kinases are causative for a wide range of human cancers, protein kinase inhibitors currently approved as cancer drugs address only a limited number of these enzymes. To identify new chemotypes addressing alternative protein kinases, the basic structure of a known PLK1/VEGF-R2 inhibitor class was formally dissected and reassembled. The resulting 7-(2-anilinopyrimidin-4-yl)-1-benzazepin-2-ones were synthesized and proved to be dual inhibitors of Aurora A kinase and VEGF receptor kinases. Crystal structures of two representatives of the new chemotype in complex with Aurora A showed the ligand orientation in the ATP binding pocket and provided the basis for rational structural modifications. Congeners with attached sulfamide substituents retained Aurora A inhibitory activity. In vitro screening of two members of the new kinase inhibitor family against the cancer cell line panel of the National Cancer Institute (NCI) showed antiproliferative activity in the single-digit micromolar concentration range in the majority of the cell lines.
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Carmena, Mar, Miguel Ortiz Lombardia, Hiromi Ogawa, and William C. Earnshaw. "Polo kinase regulates the localization and activity of the chromosomal passenger complex in meiosis and mitosis in Drosophila melanogaster." Open Biology 4, no. 11 (November 2014): 140162. http://dx.doi.org/10.1098/rsob.140162.
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Cell cycle progression is regulated by members of the cyclin-dependent kinase (CDK), Polo and Aurora families of protein kinases. The levels of expression and localization of the key regulatory kinases are themselves subject to very tight control. There is increasing evidence that crosstalk between the mitotic kinases provides for an additional level of regulation. We have previously shown that Aurora B activates Polo kinase at the centromere in mitosis, and that the interaction between Polo and the chromosomal passenger complex (CPC) component INCENP is essential in this activation. In this report, we show that Polo kinase is required for the correct localization and activity of the CPC in meiosis and mitosis. Study of the phenotype of different polo allele combinations compared to the effect of chemical inhibition revealed significant differences in the localization and activity of the CPC in diploid tissues. Our results shed new light on the mechanisms that control the activity of Aurora B in meiosis and mitosis.
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McNae, Molly, Elizabeth A. Roundhill, Susan A. Burchill, and Richard W. Bayliss. "Abstract 2015: The Aurora kinases are a potential therapeutic target in Ewing sarcoma." Cancer Research 82, no. 12_Supplement (June 15, 2022): 2015. http://dx.doi.org/10.1158/1538-7445.am2022-2015.
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Abstract The poor survival rates and limited treatment options for patients with relapsed/metastatic Ewing sarcoma (ES) highlights the need for more personalized targeted therapeutic approaches. In this project, we have investigated the prognostic potential of Aurora kinase expression in ES patients and evaluated the activity of Aurora kinase inhibitors in ES cell lines and patient derived cultures. The prognostic value of Aurora kinase A (AURKA), Aurora kinase B (AURKB) and Aurora kinase C (AURKC) was determined through interrogation of the online GSE17618 dataset using Cox models and Kaplan Meier plots. RNA seq data was obtained from the CCRG dataset for expression analysis (Roundhill et al., 2021, Cell Oncol, 44(5), 1065-85). Viable cell number was determined using the trypan blue exclusion assay on the Vi-CELL XR. Cells were treated with increasing concentrations of inhibitor (Table 1) or DMSO vehicle control for 48h. Protein was extracted after 48h for western blotting. In ES patients, high RNA expression of AURKA and AURKB is associated with a 5- and 3-fold increased risk of death respectively (n=42). Risk of an event was increased 3- or 2-fold with high expression of AURKA or AURKB respectively (n=42). High AURKC expression was not prognostic. Expression of AURKA and AURKB was confirmed at the RNA level in ES cell lines and patient derived cultures, and at the protein level in cell lines. Aurora kinase inhibitors (Table 1) decreased viable cell number of ES cell lines and patient derived cultures. Western blotting confirmed a decrease in AURKA and MYC-C expression with increasing concentration of inhibitor. AMG900 was the most potent inhibitor in TC32 cells (Table 1) and decreased viable cell number of patient derived cultures (n=5, p<0.01). High expression of AURKA or AURKB mRNA predicts poor outcome for ES patients. Inhibitors of these kinases reduce viable cell number of both ES cell lines and patient derived cultures. We are currently investigating the mechanism of action. Table 1. Summary of the effect of Aurora kinase inhibitors in TC32 ES cells. Aurora Kinase Inhibitor Concentration Range Used (nM) Target Kinases(IC50, nM) EC50 TC32 Cells (nM) (n=3) P value (EC50 AMG900 vs EC50 another inhibitor) References AMG900 1.25-50 AurA (5), AurB (4), AurC (1) + 10 kinases 1.57 N/A Payton et al., 2010, Cancer Res, 70(23), 9846-54 MLN8237 5-300 AurA (1.2), AurB (396.5) + 22 kinases 29.48 0.0468 Manfredi et al., 2011, Clin Cancer Res, 17(24), 7614-24 CCT137690 5-300 AurA (15), AurB (25), AurC (19) + 3 kinases 97.56 0.0004 Bavetsias et al., 2010, J Med Chem, 53(14), 5213-28 LY3295668 31.25-1000 AurA (0.8) AurB (1038)AurC (98) + 2 kinases Not able to calculate N/A Gong et al., 2019, Cancer Discov, 9(2), 248-263 EC50 values were calculated by nonlinear regression (GraphPad PRISM). Statistical differences between EC50 of AMG900 and the EC50 of other inhibitors were evaluated using two-way ANOVA and Tukey’s multiple comparisons test. IC50 - half maximal inhibitory concentration, EC50 - half maximal effective concentration Citation Format: Molly McNae, Elizabeth A. Roundhill, Susan A. Burchill, Richard W. Bayliss. The Aurora kinases are a potential therapeutic target in Ewing sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2015.
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Gruneberg, Ulrike, Rüdiger Neef, Reiko Honda, Erich A. Nigg, and Francis A. Barr. "Relocation of Aurora B from centromeres to the central spindle at the metaphase to anaphase transition requires MKlp2." Journal of Cell Biology 166, no. 2 (July 19, 2004): 167–72. http://dx.doi.org/10.1083/jcb.200403084.
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Mitotic kinases of the Polo and Aurora families are key regulators of chromosome segregation and cytokinesis. Here, we have investigated the role of MKlp1 and MKlp2, two vertebrate mitotic kinesins essential for cytokinesis, in the spatial regulation of the Aurora B kinase. Previously, we have demonstrated that MKlp2 recruits Polo-like kinase 1 (Plk1) to the central spindle in anaphase. We now find that in MKlp2 but not MKlp1-depleted cells the Aurora B–INCENP complex remains at the centromeres and fails to relocate to the central spindle. MKlp2 exerts dual control over Aurora B localization, because it is a binding partner for Aurora B, and furthermore for the phosphatase Cdc14A. Cdc14A can dephosphorylate INCENP and may contribute to its relocation to the central spindle in anaphase. We propose that MKlp2 is involved in the localization of Plk1, Aurora B, and Cdc14A to the central spindle during anaphase, and that the integration of signaling by these proteins is necessary for proper cytokinesis.
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Kasap, Corynn, Nicholas Hertz, Debora Makino, Kevan Shokat, John Kuriyan, and Neil P. Shah. "Beyond the Gatekeeper: Imatinib- and Dasatinib-Resistant BCR-ABL/F317 Mutations Confer Cross-Resistance to VX-680 but Are Sensitive to a Structural Derivative of VX-680." Blood 112, no. 11 (November 16, 2008): 725. http://dx.doi.org/10.1182/blood.v112.11.725.725.
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Abstract The management of chronic phase CML has been revolutionized by selective ABL tyrosine kinase inhibitor (TKI) therapy. Despite the effectiveness of these targeted agents, long-term control of blast phase CML and Ph+ ALL has been elusive, where the majority of patients relapse within 6–12 months. For blast phase CML and Ph+ ALL, two TKIs are currently approved: imatinib and dasatinib. While head-to-head comparisons of these agents have not been performed, it is generally believed that dasatinib is the more active agent for these phases of disease. In most cases, loss of response to these agents is driven by BCR-ABL kinase domain mutations. While more than 70 mutations have been associated with clinical resistance to imatinib, dasatinib appears vulnerable primarily to five mutations: V299L, T315A, T315I, F317I, and F317L. Of these, T315I and F317L are cross-resistant to imatinib. For the achievement of long-term remissions in blast phase CML and Ph+ ALL, a combination of TKIs that can collectively suppress all resistant BCR-ABL kinase domain mutations holds therapeutic promise. The BCR-ABL/T315I mutation, which confers a high degree of resistance to all approved BCR-ABL TKIs, has been referred to as a “molecular gatekeeper”, as it restricts access to a deeper hydrophobic pocket within the ABL kinase domain and makes an important stabilizing H-bond with imatinib, dasatinib and nilotinib. The Aurora kinase inhibitor VX-680 was the first compound to have activity against BCR-ABL/T315I in vitro, as well as clinically. To determine the promise of a kinase inhibitor combination of dasatinib and VX-680, we assessed the activity of VX-680 against the five dasatinib-resistant mutations using a cell-based flow cytometric assay of BCR-ABL kinase activity. While three mutants are sensitive, mutations at F317 demonstrated a high degree of resistance. We tested a number of other Aurora kinase inhibitors of different chemotypes and found that each of these had similar difficulty at inhibiting the kinase activity of BCR-ABL/F317 mutants. Based upon the co-crystal structure of VX-680 complexed with ABL, we have performed structure-activity relationship studies of 12 VX-680 scaffold derivatives, and have successfully identified structural modifications that increase kinase inhibitory activity against F317 mutants. Moreover, one of these derivatives increases the selectivity for ABL relative to Aurora kinases, which may help reduce the likelihood of suppressing normal hematopoiesis, a dose-limiting toxicity of Aurora kinase inhibitors that may substantially limit their effectiveness for the management of hematologic malignancies such as blast phase CML and Ph+ ALL. Lastly, we have performed structural studies of ABL/F317 mutants complexed with select VX-680 derivatives in an effort to understand how F317 mutations confer resistance to a broad range of ABL and Aurora kinase inhibitors. Interestingly, a recent study reported the successful selection of Aurora kinase inhibitor-resistant clones derived from a human colon cancer cell line (Girdler et al, 2008). While no resistance-conferring mutations were isolated at L154, the Aurora kinase gatekeeper residue, mutations were detected at Y156 in Aurora B, which corresponds to F317 in ABL. Aurora B Y156 mutations were found to confer resistance to a number of Aurora kinase inhibitors, including VX-680. As Aurora kinase inhibitors are being studied in a variety of non-hematologic malignancies, there is an increasing need to understand and overcome the mechanisms whereby mutations at this residue confer resistance to these agents. It is hoped that our studies will lead not only to the development of an effective adjunctive kinase inhibitor for the treatment of blast phase CML and Ph+ ALL, but will also shed light on the growing problem of resistance conferred by mutations at residues that correspond to BCR-ABL/F317 in other kinases.
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Islam, Saiful, Theodosia Teo, Malika Kumarasiri, Martin Slater, Jennifer H. Martin, Shudong Wang, and Richard Head. "Combined In Silico and In Vitro Evidence Supporting an Aurora A Kinase Inhibitory Role of the Anti-Viral Drug Rilpivirine and an Anti-Proliferative Influence on Cancer Cells." Pharmaceuticals 15, no. 10 (September 25, 2022): 1186. http://dx.doi.org/10.3390/ph15101186.
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The global burden of cancer necessitates rapid and ongoing development of effective cancer therapies. One promising approach in this context is the repurposing of existing non-cancer drugs for cancer indications. A key to this approach is selecting the cellular targets against which to identify novel repurposed drugs for pre-clinical analysis. Protein kinases are highly sought-after anticancer drug targets since dysregulation of kinases is the hallmark of cancer. To identify potential kinase-targeted drug candidates from the existing portfolio of non-cancer therapeutics, we used combined in silico and in vitro approaches, including ligand-based 3D screening followed by biochemical and cellular assessments. This strategy revealed that the anti-viral drug rilpivirine is an Aurora A kinase inhibitor. In view of previous findings implicating Aurora A kinase in abnormal cell cycle regulation, we also examined the influence of rilpivirine on the growth of T47D breast cancer cells. Herein, we detail the identification of rilpivirine as an Aurora A kinase inhibitor, its molecular basis of inhibitory activity towards this kinase, and its Aurora A-mediated anticancer mechanisms in T47D cells. Our results illustrate the value of integrated in silico and in vitro screening strategies in identifying repurposed drug candidates and provide a scientific basis for further exploring the potential anticancer properties of the anti-viral drug rilpivirine.
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Karthigeyan, Dhanasekan, Arnab Bose, Ramachandran Boopathi, Vinay Jaya Rao, Hiroki Shima, Narendra Bharathy, Kazuhiko Igarashi, Reshma Taneja, Arun Kumar Trivedi, and Tapas K. Kundu. "Aurora kinase A-mediated phosphorylation of mPOU at a specific site drives skeletal muscle differentiation." Journal of Biochemistry 167, no. 2 (October 30, 2019): 195–201. http://dx.doi.org/10.1093/jb/mvz088.
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Abstract Aurora kinases are Ser/Thr-directed protein kinases which play pivotal roles in mitosis. Recent evidences highlight the importance of these kinases in multiple biological events including skeletal muscle differentiation. Our earlier study identified the transcription factor POU6F1 (or mPOU) as a novel Aurora kinase (Aurk) A substrate. Here, we report that Aurora kinase A phosphorylates mPOU at Ser197 and inhibit its DNA-binding ability. Delving into mPOU physiology, we find that the phospho-mimic (S197D) mPOU mutant exhibits enhancement, while the wild type or the phospho-deficient mutant shows retardation in C2C12 myoblast differentiation. Interestingly, POU6F1 depletion phenocopies S197D-mPOU overexpression in the differentiation context. Collectively, our results signify mPOU as a negative regulator of skeletal muscle differentiation and strengthen the importance of AurkA in skeletal myogenesis.
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Honda, Reiko, Roman Körner, and Erich A. Nigg. "Exploring the Functional Interactions between Aurora B, INCENP, and Survivin in Mitosis." Molecular Biology of the Cell 14, no. 8 (August 2003): 3325–41. http://dx.doi.org/10.1091/mbc.e02-11-0769.
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The function of the Aurora B kinase at centromeres and the central spindle is crucial for chromosome segregation and cytokinesis, respectively. Herein, we have investigated the regulation of human Aurora B by its complex partners inner centromere protein (INCENP) and survivin. We found that overexpression of a catalytically inactive, dominant-negative mutant of Aurora B impaired the localization of the entire Aurora B/INCENP/survivin complex to centromeres and the central spindle and severely disturbed mitotic progression. Similar results were also observed after depletion, by RNA interference, of either Aurora B, INCENP, or survivin. These data suggest that Aurora B kinase activity and the formation of the Aurora B/INCENP/survivin complex both contribute to its proper localization. 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. Under identical assay conditions, survivin did not detectably influence kinase activity. Human INCENP was a substrate of Aurora B and mass spectrometry identified three consecutive residues (threonine 893, serine 894, and serine 895) containing at least two phosphorylation sites. A nonphosphorylatable mutant (TSS893–895AAA) was a poor activator of Aurora B, demonstrating that INCENP phosphorylation is important for kinase activation.
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Gallaud, Emmanuel, Laurent Richard-Parpaillon, Laetitia Bataillé, Aude Pascal, Mathieu Métivier, Vincent Archambault, and Régis Giet. "The spindle assembly checkpoint and the spatial activation of Polo kinase determine the duration of cell division and prevent tumor formation." PLOS Genetics 18, no. 4 (April 4, 2022): e1010145. http://dx.doi.org/10.1371/journal.pgen.1010145.
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The maintenance of a restricted pool of asymmetrically dividing stem cells is essential for tissue homeostasis. This process requires the control of mitotic progression that ensures the accurate chromosome segregation. In addition, this event is coupled to the asymmetric distribution of cell fate determinants in order to prevent stem cell amplification. How this coupling is regulated remains poorly described. Here, using asymmetrically dividing Drosophila neural stem cells (NSCs), we show that Polo kinase activity levels determine timely Cyclin B degradation and mitotic progression independent of the spindle assembly checkpoint (SAC). This event is mediated by the direct phosphorylation of Polo kinase by Aurora A at spindle poles and Aurora B kinases at centromeres. Furthermore, we show that Aurora A-dependent activation of Polo is the major event that promotes NSC polarization and together with the SAC prevents brain tumor growth. Altogether, our results show that an Aurora/Polo kinase module couples NSC mitotic progression and polarization for tissue homeostasis.
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Platani, Melpomeni, Laura Trinkle-Mulcahy, Michael Porter, A. Arockia Jeyaprakash, and William C. Earnshaw. "Mio depletion links mTOR regulation to Aurora A and Plk1 activation at mitotic centrosomes." Journal of Cell Biology 210, no. 1 (June 29, 2015): 45–62. http://dx.doi.org/10.1083/jcb.201410001.
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Coordination of cell growth and proliferation in response to nutrient supply is mediated by mammalian target of rapamycin (mTOR) signaling. In this study, we report that Mio, a highly conserved member of the SEACAT/GATOR2 complex necessary for the activation of mTORC1 kinase, plays a critical role in mitotic spindle formation and subsequent chromosome segregation by regulating the proper concentration of active key mitotic kinases Plk1 and Aurora A at centrosomes and spindle poles. Mio-depleted cells showed reduced activation of Plk1 and Aurora A kinase at spindle poles and an impaired localization of MCAK and HURP, two key regulators of mitotic spindle formation and known substrates of Aurora A kinase, resulting in spindle assembly and cytokinesis defects. Our results indicate that a major function of Mio in mitosis is to regulate the activation/deactivation of Plk1 and Aurora A, possibly by linking them to mTOR signaling in a pathway to promote faithful mitotic progression.
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MACHADO, CAIO BEZERRA, EMERSON LUCENA DA SILVA, BEATRIZ MARIA DIAS NOGUEIRA, JEAN BRENO SILVEIRA DA SILVA, MANOEL ODORICO DE MORAES FILHO, RAQUEL CARVALHO MONTENEGRO, MARIA ELISABETE AMARAL DE MORAES, and CAROLINE AQUINO MOREIRA-NUNES. "The Relevance of Aurora Kinase Inhibition in Hematological Malignancies." Cancer Diagnosis & Prognosis 1, no. 3 (July 3, 2021): 111–26. http://dx.doi.org/10.21873/cdp.10016.
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Aurora kinases are a family of serine/threonine protein kinases that play a central role in eukaryotic cell division. Overexpression of aurora kinases in cancer and their role as major regulators of the cell cycle quickly inspired the idea that their inhibition might be a potential pathway when treating oncologic patients. Over the past couple of decades, the search for designing and testing of molecules capable of inhibiting aurora activities fueled many pre-clinical and clinical studies. In this study, data from the past 10 years of in vitro and in vivo investigations, as well as clinical trials, utilizing aurora kinase inhibitors as therapeutics for hematological malignancies were compiled and discussed, aiming to highlight potential uses of these inhibitors as a novel monotherapy model or alongside conventional chemotherapies. While there is still much to be elucidated, it is clear that these kinases play a key role in oncogenesis, and their manageable toxicity and potentially synergistic effects still render them a focus of interest for future investigations in combinatorial clinical trials
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Bolton, Margaret A., Weijie Lan, Shannon E. Powers, Mark L. McCleland, Jian Kuang, and P. Todd Stukenberg. "Aurora B Kinase Exists in a Complex with Survivin and INCENP and Its Kinase Activity Is Stimulated by Survivin Binding and Phosphorylation." Molecular Biology of the Cell 13, no. 9 (September 2002): 3064–77. http://dx.doi.org/10.1091/mbc.e02-02-0092.
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Aurora B regulates chromosome segregation and cytokinesis and is the first protein to be implicated as a regulator of bipolar attachment of spindle microtubules to kinetochores. Evidence from several systems suggests that Aurora B is physically associated with inner centromere protein (INCENP) in mitosis and has genetic interactions with Survivin. It is unclear whether the Aurora B and INCENP interaction is cell cycle regulated and if Survivin physically interacts in this complex. In this study, we cloned theXenopus Survivin gene, examined its association with Aurora B and INCENP, and determined the effect of its binding on Aurora B kinase activity. We demonstrate that in the Xenopusearly embryo, all of the detectable Survivin is in a complex with both Aurora B and INCENP throughout the cell cycle. Survivin and Aurora B bind different domains on INCENP. Aurora B activity is stimulated >10-fold in mitotic extracts; this activation is phosphatase sensitive, and the binding of Survivin is required for full Aurora B activity. We also find the hydrodynamic properties of the Aurora B/Survivin/INCENP complex are cell cycle regulated. Our data indicate that Aurora B kinase activity is regulated by both Survivin binding and cell cycle-dependent phosphorylation.
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Ikezoe, Takayuki, Chie Nishioka, Taizo Tasaka, Ayuko Taniguchi, Naoki Komatsu, Yoshio Kuwayama, Kazuto Togitani, H. Phillip Koeffler, and Hirokuni Taguchi. "ZM447439, a Novel Aurora Kinase Inhibitor, Induces Growth Arrest and Apoptosis of Human Leukemia Cells." Blood 108, no. 11 (November 16, 2006): 1990. http://dx.doi.org/10.1182/blood.v108.11.1990.1990.
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Abstract The Aurora kinases play an important role in chromosome alignment, segregation, and cytokinesis during mitosis. Aberrant expression of these kinases have been shown in solid tumors and considered to associate with aneuploidy and carcinogenesis. This study found that Aurora kinase A and B were aberrantly expressed in human leukemia cell lines (n=15, e.g., PALL-1, -2, HL-60, NB4, MV4-11, etc.) as well as freshly isolated leukemia cells from individuals with acute myeloid leukemia (n=44) compared to peripheral blood mononuclear cells from healthy volunteers (n=12), as measured by real-time PCR. In addition, ZM447439, a novel selective Aurora kinase inhibitor, induced growth inhibition, accumulation of cells with 4N DNA content and apoptosis in human leukemia cells as measured by thymidine-uptake, cell cycle analysis and annexin V staining, respectively. Especially, profound growth inhibition occurred in PALL-1 and -2 cells which possess wild-type p53 gene. Of note, ZM447439 did not inhibit clonogenic growth of myeloid committed stem cells harvested from healthy volunteers. Taken together, inhibition of Aurora kinase may be a promising treatment strategy for the individuals with leukemia.
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Moore, Andrew S., Amir Faisal, Vassilios Bavetsias, Chongbo Sun, Butrus Atrash, Melanie Valenti, Alexis de Haven Brandon, et al. "Dual Inhibition of Aurora and FLT3 Kinases by CCT137690: A Novel Treatment Strategy Against FLT3-ITD Positive AML In Vitro and In Vivo." Blood 116, no. 21 (November 19, 2010): 3289. http://dx.doi.org/10.1182/blood.v116.21.3289.3289.
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Abstract Abstract 3289 The Aurora kinases are a family of serine-threonine kinases that play key roles in different stages of mitosis. Over-expression of Aurora kinases has been demonstrated in a range of malignancies including leukemia. Aurora kinase inhibitors are emerging as promising agents in the treatment of acute myeloid leukemia (AML) with a number of compounds currently being assessed in clinical trials (Moore AS et al, Leukemia 2010). CCT137690, an imidazo[4,5-b]pyridine derivative discovered at our Institute, is an orally bioavailable, potent, pan-Aurora and FLT3 inhibitor with low nanomolar IC50 values against Aurora A (15 nM), Aurora B (25 nM), Aurora C (19 nM), and FLT3 (<0.5 nM) kinases. CCT137690 showed in vitro and in vivo activity in human colon cancer cell lines and xenograft models (Bavetsias V et al, J Med Chem 2010). Here we report the in vitro and in vivo activity of CCT137690 in FLT3-ITD positive AML. In vitro, the FLT3-ITD positive cell lines MV-4-11 and MOLM-13 are particularly sensitive with GI50 values less than 50 nM. Cellular assays demonstrate that CCT137690 inhibits autophosphorylation of Aurora A, Aurora B and Aurora C kinases and phosphorylation of histone H3, a direct target of Aurora B kinase. CCT137690 also inhibits autophosphorylation of FLT3 and phosphorylation of its downstream targets STAT5 and p44/42 MAPK (Erk1/2). Dual inhibition of Aurora and FLT3 kinases in FLT3-ITD positive AML with CCT137690 induces apoptosis and results in a unique cell cycle profile with cells accumulating in G2/M, whilst selective FLT3 inhibition with MLN518 resulted in G1/S arrest. When given orally to athymic mice, CCT137690 achieved target modulation and potently inhibited the growth of subcutaneous MOLM-13 xenografts, with no obvious toxicity or loss of body weight. Inhibition of MOLM-13 xenograft growth was more pronounced with CCT137690 compared to the selective FLT3 inhibitor MLN518, suggesting that dual inhibition of Aurora and FLT3 kinases may have advantages compared to selective FLT3 inhibition alone. The potent preclinical activity of CCT137690 in FLT3-ITD positive AML models supports the growing body of evidence that dual pan-Aurora and FLT3 kinase inhibitors may be of benefit in the high-risk group of patients with FLT3-ITD positive AML. Disclosures: Moore: The Institute of Cancer Research: Employment, The Institute of Cancer Research (ICR) has a commercial interest in drug development programs. Authors employed by ICR are subject to a Rewards to Inventors Scheme, which may reward contributors to a program that is subsequently licensed. Faisal:The Institute of Cancer Research: Employment. Bavetsias:The Institute of Cancer Research: Employment. Sun:The Institute of Cancer Research: Employment. Atrash:The Institute of Cancer Research: Employment. Valenti:The Institute of Cancer Research: Employment. de Haven Brandon:The Institute of Cancer Research: Employment. Avery:The Institute of Cancer Research: Employment. Raynaud:The Institute of Cancer Research: Employment. Workman:The Institute of Cancer Research: Employment. Pearson:The Institute of Cancer Research: Employment. Blagg:The Institute of Cancer Research: Employment. Eccles:The Institute of Cancer Research: Employment. Linardopoulos:The Institute of Cancer Research: Employment.
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Petersen, Janni, Jeannie Paris, Martin Willer, Michel Philippe, and Iain M. Hagan. "TheS. pombeaurora-related kinase Ark1 associates with mitotic structures in a stage dependent manner and is required for chromosome segregation." Journal of Cell Science 114, no. 24 (December 15, 2001): 4371–84. http://dx.doi.org/10.1242/jcs.114.24.4371.
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Metazoans contain three aurora-related kinases. Aurora A is required for spindle formation while aurora B is required for chromosome condensation and cytokinesis. Less is known about the function of aurora C. S. pombe contains a single aurora-related kinase, Ark1. Although Ark1 protein levels remained constant as cells progressed through the mitotic cell cycle, its distribution altered during mitosis and meiosis. Throughout G2 Ark1 was concentrated in one to three nuclear foci that were not associated with the spindle pole body/centromere complex. Following commitment to mitosis Ark1 associated with chromatin and was particularly concentrated at several sites including kinetochores/centromeres. Kinetochore/centromere association diminished during anaphase A, after which it was distributed along the spindle. The protein became restricted to a small central zone that transiently enlarged as the spindle extended. As in many other systems mitotic fission yeast cells exhibit a much greater degree of phosphorylation of serine 10 of histone H3 than interphase cells. A number of studies have linked this modification with chromosome condensation. Ark1 immuno-precipitates phosphorylated serine 10 of histone H3 in vitro. This activity was highest in mitotic extracts. The absence of the histone H3 phospho-serine 10 epitope from mitotic cells in which the ark1+ gene had been deleted (ark1.Δ1); the inability of these cells to resolve their chromosomes during anaphase and the co-localisation of this phospho-epitope with Ark1 early in mitosis, all suggest that Ark1 phosphorylates serine 10 of histone H3 in vivo. ark1.Δ1 cells also exhibited a reduction in kinetochore activity and a minor defect in spindle formation. Thus the enzyme activity, localisation and phenotype arising from our manipulations of this single fission yeast aurora kinase family member suggest that this single kinase is executing functions that are separately implemented by distinct aurora A and aurora B kinases in higher systems.
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Galetta, Domenico, and Lourdes Cortes-Dericks. "Promising Therapy in Lung Cancer: Spotlight on Aurora Kinases." Cancers 12, no. 11 (November 14, 2020): 3371. http://dx.doi.org/10.3390/cancers12113371.
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Despite tremendous efforts to improve the treatment of lung cancer, prognosis still remains poor; hence, the search for efficacious therapeutic option remains a prime concern in lung cancer research. Cell cycle regulation including mitosis has emerged as an important target for cancer management. Novel pharmacological agents blocking the activities of regulatory molecules that control the functional aspects of mitosis such as Aurora kinases are now being investigated. The Aurora kinases, Aurora-A (AURKA), and Aurora B (AURKB) are overexpressed in many tumor entities such as lung cancer that correlate with poor survival, whereby their inhibition, in most cases, enhances the efficacy of chemo-and radiotherapies, indicating their implication in cancer therapy. The current knowledge on Aurora kinase inhibitors has increasingly shown high potential in ensuing targeted therapies in lung malignancies. In this review, we will briefly describe the biology of Aurora kinases, highlight their oncogenic roles in the pre-clinical and clinical studies in lung cancer and, finally, address the challenges and potentials of Aurora kinases to improve the therapy of this malignancy.
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Ding, Yali, Chunhua Song, Joseph Schramm, Soumya Maru, Daniel Bogus, Dhimant H. Desai, Arati K. Sharma, Chandrika Gowda, and Sinisa Dovat. "Abstract 846: Transcriptional regulation of Aurora-B kinase expression in B-cell acute lymphoblastic leukemia (B-ALL)." Cancer Research 82, no. 12_Supplement (June 15, 2022): 846. http://dx.doi.org/10.1158/1538-7445.am2022-846.
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Abstract The Aurora kinases are serine/threonine kinases that are essential for mitosis. Aurora-B kinase is a component of the chromosomal passenger complex (CPC), chromosome condensation, the spindle-assembly checkpoint, and for cytokinesis. The activity of Aurora-B is essential for cellular division and proliferation. Inhibition of Aurora-B is cytotoxic, and inhibitor of Aurora-B - Barasertib (AZD1152) has been tested in clinical trials against different types of malignancies, including leukemia. However, regulation of Aurora-B expression is still largely unknown. Here, we present evidence that expression of Aurora-B in B-cell acute lymphoblastic leukemia (B-ALL) is regulated at the transcriptional level by Ikaros, a transcription factor and tumor suppressor protein. Analysis of global chromatin immunoprecipitation coupled with next-generation sequencing (ChIP-seq) in several B-ALL primary human B-ALL cells and cell lines, showed a strong enrichment of Ikaros at the promoter of the Aurora-B gene. Ikaros functions as a tumor suppressor protein and deletion of Ikaros is associated with development of high-risk B-ALL. Ikaros binding to Aurora-B promoter was confirmed by quantitative chromatin immunoprecipitation (qChIP) in primary B-ALL cells. The role of Ikaros in regulating Aurora-B transcription in B-ALL was tested using gain-of-function and loss-of-function experiments. Overexpression of Ikaros in human B-ALL was associated with strongly reduced transcription and overall expression of Aurora-B. Ikaros knock-down with shRNA results in increased expression of Aurora-B in B-ALL. Since Ikaros function in B-ALL is negatively regulated by pro-oncogenic Casein Kinase II (CK2), we tested whether CK2 can regulate expression of Aurora-B in B-ALL. Overexpression of CK2 via retroviral transduction resulted in increased expression of the Aurora-B gene. Increased expression of CK2 was associated with a loss of Ikaros binding to the Aurora-B gene promoter. Molecular inhibition of CK2 using shRNA resulted in reduced expression of Aurora-B in human B-ALL. Inhibition of CK2 was associated with increased Ikaros binding at the Aurora-B promoter. Ikaros knock-down abolished downregulation of Aurora-B expression in B-ALL cells following treatment with CK2 inhibitors. These data demonstrate that CK2 and Ikaros are critical regulators of Aurora-B expression in B-ALL. In conclusion, these results indicate that expression of the Aurora-B gene in B-ALL is regulated by the CK2-Ikaros signaling axis and provide a novel insight into mechanisms that regulate mitosis in leukemia. Citation Format: Yali Ding, Chunhua Song, Joseph Schramm, Soumya Maru, Daniel Bogus, Dhimant H. Desai, Arati K. Sharma, Chandrika Gowda, Sinisa Dovat. Transcriptional regulation of Aurora-B kinase expression in B-cell acute lymphoblastic leukemia (B-ALL) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 846.