scholarly journals Haspin inhibition reveals functional differences of interchromatid axis–localized AURKB and AURKC

2017 ◽  
Vol 28 (17) ◽  
pp. 2233-2240 ◽  
Author(s):  
Suzanne M. Quartuccio ◽  
Shweta S. Dipali ◽  
Karen Schindler
Keyword(s):  
Chromosome Segregation ◽  
Spindle Assembly Checkpoint ◽  
Aurora Kinase ◽  
Genetic Abnormality ◽  
Aurora Kinase B ◽  
Kinase C ◽  
Functional Differences ◽  
Chromosomal Passenger ◽  
Functional Capacities ◽  
Meiosis I

Aneuploidy is the leading genetic abnormality contributing to infertility, and chromosome segregation errors are common during female mammalian meiosis I (MI). Previous results indicate that haspin kinase regulates resumption of meiosis from prophase arrest, chromosome condensation, and kinetochore–microtubule attachments during early prometaphase of MI. Here we report that haspin inhibition in late prometaphase I causes acceleration of MI, bypass of the spindle assembly checkpoint (SAC), and loss of interchromatid axis–localized Aurora kinase C. Meiotic cells contain a second chromosomal passenger complex (CPC) population, with Aurora kinase B (AURKB) bound to INCENP. Haspin inhibition in oocytes from Aurkc−/− mice, where AURKB is the sole CPC kinase, does not alter MI completion timing, and no change in localization of the SAC protein, MAD2, is observed. These data suggest that AURKB on the interchromatid axis is not needed for SAC activation and illustrate a key difference between the functional capacities of the two AURK homologues.

scholarly journals Aurora Kinase B Inhibition: A Potential Therapeutic Strategy for Cancer

Molecules ◽  
2021 ◽  
Vol 26 (7) ◽  
pp. 1981
Author(s):  
Naheed Arfin Borah ◽  
Mamatha M. Reddy
Keyword(s):  
Drug Resistance ◽  
Cell Cycle Progression ◽  
Therapeutic Strategy ◽  
Tumor Development ◽  
Aurora Kinase ◽  
Aurora Kinase B ◽  
Development Therapy ◽  
Chromosomal Passenger ◽  
Combination Studies ◽  
Related Drug

Aurora kinase B (AURKB) is a mitotic serine/threonine protein kinase that belongs to the aurora kinase family along with aurora kinase A (AURKA) and aurora kinase C (AURKC). AURKB is a member of the chromosomal passenger protein complex and plays a role in cell cycle progression. Deregulation of AURKB is observed in several tumors and its overexpression is frequently linked to tumor cell invasion, metastasis and drug resistance. AURKB has emerged as an attractive drug target leading to the development of small molecule inhibitors. This review summarizes recent findings pertaining to the role of AURKB in tumor development, therapy related drug resistance, and its inhibition as a potential therapeutic strategy for cancer. We discuss AURKB inhibitors that are in preclinical and clinical development and combination studies of AURKB inhibition with other therapeutic strategies.

scholarly journals Bub1, Sgo1, and Mps1 mediate a distinct pathway for chromosome biorientation in budding yeast

2011 ◽  
Vol 22 (9) ◽  
pp. 1473-1485 ◽  
Author(s):  
Zuzana Storchová ◽  
Justin S. Becker ◽  
Nicolas Talarek ◽  
Sandra Kögelsberger ◽  
David Pellman
Keyword(s):  
Chromosome Segregation ◽  
Spindle Assembly Checkpoint ◽  
Budding Yeast ◽  
Spindle Pole ◽  
Growth Defect ◽  
Aurora B ◽  
Mitotic Kinase ◽  
Sister Chromatids ◽  
Chromosome Alignment ◽  
Chromosomal Passenger

The conserved mitotic kinase Bub1 performs multiple functions that are only partially characterized. Besides its role in the spindle assembly checkpoint and chromosome alignment, Bub1 is crucial for the kinetochore recruitment of multiple proteins, among them Sgo1. Both Bub1 and Sgo1 are dispensable for growth of haploid and diploid budding yeast, but they become essential in cells with higher ploidy. We find that overexpression of SGO1 partially corrects the chromosome segregation defect of bub1Δ haploid cells and restores viability to bub1Δ tetraploid cells. Using an unbiased high-copy suppressor screen, we identified two members of the chromosomal passenger complex (CPC), BIR1 (survivin) and SLI15 (INCENP, inner centromere protein), as suppressors of the growth defect of both bub1Δ and sgo1Δ tetraploids, suggesting that these mutants die due to defects in chromosome biorientation. Overexpression of BIR1 or SLI15 also complements the benomyl sensitivity of haploid bub1Δ and sgo1Δ cells. Mutants lacking SGO1 fail to biorient sister chromatids attached to the same spindle pole (syntelic attachment) after nocodazole treatment. Moreover, the sgo1Δ cells accumulate syntelic attachments in unperturbed mitoses, a defect that is partially corrected by BIR1 or SLI15 overexpression. We show that in budding yeast neither Bub1 nor Sgo1 is required for CPC localization or affects Aurora B activity. Instead we identify Sgo1 as a possible partner of Mps1, a mitotic kinase suggested to have an Aurora B–independent function in establishment of biorientation. We found that Sgo1 overexpression rescues defects caused by metaphase inactivation of Mps1 and that Mps1 is required for Sgo1 localization to the kinetochore. We propose that Bub1, Sgo1, and Mps1 facilitate chromosome biorientation independently of the Aurora B–mediated pathway at the budding yeast kinetochore and that both pathways are required for the efficient turnover of syntelic attachments.

scholarly journals Spindle checkpoint activation at meiosis I advances anaphase II onset via meiosis-specific APC/C regulation

2008 ◽  
Vol 182 (2) ◽  
pp. 277-288 ◽  
Author(s):  
Ayumu Yamamoto ◽  
Kenji Kitamura ◽  
Daisuke Hihara ◽  
Yukinobu Hirose ◽  
Satoshi Katsuyama ◽  
...  
Keyword(s):  
Protein Degradation ◽  
Fission Yeast ◽  
Chromosome Segregation ◽  
Spindle Assembly Checkpoint ◽  
Related Factor ◽  
Anaphase Promoting Complex ◽  
Checkpoint Activation ◽  
Anaphase Onset ◽  
Yeast Meiosis ◽  
Meiosis I

During mitosis, the spindle assembly checkpoint (SAC) inhibits the Cdc20-activated anaphase-promoting complex/cyclosome (APC/CCdc20), which promotes protein degradation, and delays anaphase onset to ensure accurate chromosome segregation. However, the SAC function in meiotic anaphase regulation is poorly understood. Here, we examined the SAC function in fission yeast meiosis. As in mitosis, a SAC factor, Mad2, delayed anaphase onset via Slp1 (fission yeast Cdc20) when chromosomes attach to the spindle improperly. However, when the SAC delayed anaphase I, the interval between meiosis I and II shortened. Furthermore, anaphase onset was advanced and the SAC effect was reduced at meiosis II. The advancement of anaphase onset depended on a meiosis-specific, Cdc20-related factor, Fzr1/Mfr1, which contributed to anaphase cyclin decline and anaphase onset and was inefficiently inhibited by the SAC. Our findings show that impacts of SAC activation are not confined to a single division at meiosis due to meiosis-specific APC/C regulation, which has probably been evolved for execution of two meiotic divisions.

scholarly journals The Aurora Kinase C c.144delC mutation causes meiosis I arrest in men and is frequent in the North African population

2009 ◽  
Vol 18 (7) ◽  
pp. 1301-1309 ◽  
Author(s):  
K. Dieterich ◽  
R. Zouari ◽  
R. Harbuz ◽  
F. Vialard ◽  
D. Martinez ◽  
...  
Keyword(s):  
Aurora Kinase ◽  
African Population ◽  
North African ◽  
The North ◽  
Kinase C ◽  
North African Population ◽  
Meiosis I

scholarly journals Evolution, Expression and Meiotic Behavior of Genes Involved in Chromosome Segregation of Monotremes

Genes ◽  
2021 ◽  
Vol 12 (9) ◽  
pp. 1320
Author(s):  
Filip Pajpach ◽  
Linda Shearwin-Whyatt ◽  
Frank Grützner
Keyword(s):  
Chromosome Segregation ◽  
Sex Chromosome ◽  
Current Model ◽  
Aurora Kinase ◽  
Egg Laying ◽  
Aurora Kinase B ◽  
Specific Distribution ◽  
Mammalian Lineage ◽  
Chromosome Passenger Complex ◽  
Mitosis And Meiosis

Chromosome segregation at mitosis and meiosis is a highly dynamic and tightly regulated process that involves a large number of components. Due to the fundamental nature of chromosome segregation, many genes involved in this process are evolutionarily highly conserved, but duplications and functional diversification has occurred in various lineages. In order to better understand the evolution of genes involved in chromosome segregation in mammals, we analyzed some of the key components in the basal mammalian lineage of egg-laying mammals. The chromosome passenger complex is a multiprotein complex central to chromosome segregation during both mitosis and meiosis. It consists of survivin, borealin, inner centromere protein, and Aurora kinase B or C. We confirm the absence of Aurora kinase C in marsupials and show its absence in both platypus and echidna, which supports the current model of the evolution of Aurora kinases. High expression of AURKBC, an ancestor of AURKB and AURKC present in monotremes, suggests that this gene is performing all necessary meiotic functions in monotremes. Other genes of the chromosome passenger complex complex are present and conserved in monotremes, suggesting that their function has been preserved in mammals. Cohesins are another family of genes that are of vital importance for chromosome cohesion and segregation at mitosis and meiosis. Previous work has demonstrated an accumulation and differential loading of structural maintenance of chromosomes 3 (SMC3) on the platypus sex chromosome complex at meiotic prophase I. We investigated if a similar accumulation occurs in the echidna during meiosis I. In contrast to platypus, SMC3 was only found on the synaptonemal complex in echidna. This indicates that the specific distribution of SMC3 on the sex chromosome complex may have evolved specifically in platypus.

scholarly journals Screening of diverse phytochemicals with Aurora Kinase C protein: An In Silico approach

2019 ◽  
Vol 9 (1-s) ◽  
pp. 67-74
Author(s):  
Pujan N Pandya ◽  
Archana U Mankad ◽  
Rakesh M Rawal ◽  
Kumar S Prasanth
Keyword(s):  
Research Work ◽  
Cancer Therapeutics ◽  
Aurora Kinase ◽  
Ligand Complex ◽  
Over Expression ◽  
Natural Ligand ◽  
Kinase C ◽  
Important Target ◽  
Chromosomal Passenger ◽  
Ligand Interactions

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

scholarly journals Cell-based screen for altered nuclear phenotypes reveals senescence progression in polyploid cells after Aurora kinase B inhibition

2015 ◽  
Vol 26 (17) ◽  
pp. 2971-2985 ◽  
Author(s):  
Mahito Sadaie ◽  
Christian Dillon ◽  
Masashi Narita ◽  
Andrew R. J. Young ◽  
Claire J. Cairney ◽  
...  
Keyword(s):  
Spindle Assembly Checkpoint ◽  
Kinase Inhibitor ◽  
Aurora Kinase ◽  
Small Population ◽  
Aurora Kinase B ◽  
Human Diploid Fibroblasts ◽  
Oncogenic Ras ◽  
Chromosome Passenger Complex ◽  
Progressive Accumulation

Cellular senescence is a widespread stress response and is widely considered to be an alternative cancer therapeutic goal. Unlike apoptosis, senescence is composed of a diverse set of subphenotypes, depending on which of its associated effector programs are engaged. Here we establish a simple and sensitive cell-based prosenescence screen with detailed validation assays. We characterize the screen using a focused tool compound kinase inhibitor library. We identify a series of compounds that induce different types of senescence, including a unique phenotype associated with irregularly shaped nuclei and the progressive accumulation of G1 tetraploidy in human diploid fibroblasts. Downstream analyses show that all of the compounds that induce tetraploid senescence inhibit Aurora kinase B (AURKB). AURKB is the catalytic component of the chromosome passenger complex, which is involved in correct chromosome alignment and segregation, the spindle assembly checkpoint, and cytokinesis. Although aberrant mitosis and senescence have been linked, a specific characterization of AURKB in the context of senescence is still required. This proof-of-principle study suggests that our protocol is capable of amplifying tetraploid senescence, which can be observed in only a small population of oncogenic RAS-induced senescence, and provides additional justification for AURKB as a cancer therapeutic target.

scholarly journals Aurora kinase Ipl1 facilitates bilobed distribution of clustered kinetochores to ensure error-free chromosome segregation in Candida albicans

2019 ◽  
Author(s):  
Neha Varshney ◽  
Kaustuv Sanyal
Keyword(s):  
Candida Albicans ◽  
Chromosome Segregation ◽  
Structural Integrity ◽  
Aurora Kinase ◽  
Spindle Pole ◽  
Microtubule Dynamics ◽  
Aurora Kinase B ◽  
Spindle Pole Bodies ◽  
Candida Infections ◽  
Anti Fungal

Candida albicans, an ascomycete, has an ability to switch to diverse morphological forms. While C. albicans is predominatly diploid, it can tolerate aneuploidy as a survival strategy under stress. Aurora kinase B homolog Ipl1 is a critical ploidy regulator that controls microtubule dynamics and chromosome segregation in Saccharomyces cerevisiae. In this study, we show that Ipl1 in C. albicans has a longer activation loop than that of the well-studied ascomycete S. cerevisiae. Ipl1 localizes to the kinetochores during the G1/S phase and associates with the spindle during mitosis. Ipl1 regulates cell morphogenesis and is required for cell viability. Ipl1 monitors microtubule dynamics which is mediated by separation of spindle pole bodies. While Ipl1 is dispensable for maintaining structural integrity and clustering of kinetochores in C. albicans, it is required for the maintenance of kinetochore geometry to form bilobed structures along the mitotic spindle, a feature of Ipl1 that was not observed in other yeasts. Depletion of Ipl1 results in erroneous kinetochore-microtubule attachments leading to aneuploidy-associated resistance to fluconazole, the most common anti-fungal drug used to treat Candida infections. Taking together, we suggest that Ipl1 spatiotemporally ensures kinetochore geometry to facilitate bipolar spindle assembly crucial for ploidy maintenance in C. albicans.

scholarly journals Aurora kinase B inhibits Aurora kinase A to control maternal mRNA translation in mouse oocytes

Development ◽  
2021 ◽  
Author(s):  
Mansour Aboelenain ◽  
Karen Schindler
Keyword(s):  
Mrna Translation ◽  
Aurora Kinase ◽  
Cytoplasmic Polyadenylation ◽  
Aurora Kinase A ◽  
Aurora Kinase B ◽  
Maternal Mrna ◽  
Kinase C ◽  
Maternal Mrnas ◽  
Mrna Polyadenylation ◽  
Kinase A

Mammalian oocytes are transcriptionally quiescent, and meiosis and early embryonic divisions rely on translation of stored maternal mRNAs. Activation of these mRNAs is mediated by polyadenylation. Cytoplasmic polyadenylation binding element 1 (CPEB1) regulates activates mRNA polyadenylation. One message is Aurora kinase C (Aurkc), encoding a protein that regulates chromosome segregation. We previously demonstrated that AURKC levels are upregulated in oocytes lacking Aurora kinase B (AURKB), and this upregulation caused increased aneuploidy rates, a role we investigate here. Using genetic and pharmacologic approaches, we found that AURKB negatively regulates CPEB1-dependent translation of many messages. To determine why translation is increased, we evaluated Aurora kinase A (AURKA), a kinase that activates CPEB1 in other organisms. We find that AURKA activity is increased in Aurkb knockout oocytes and demonstrate that this increase drives the excess translation. Importantly, removal of one copy of Aurka from the Aurkb knockout strain background, reduces aneuploidy rates. This study demonstrates that AURKA is required for CPEB1-dependent translation, and it describes a new AURKB requirement to maintain translation levels through AURKA, a function critical to generating euploid eggs.

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