scholarly journals Aurora B couples chromosome alignment with anaphase by targeting BubR1, Mad2, and Cenp-E to kinetochores

2003 ◽  
Vol 161 (2) ◽  
pp. 267-280 ◽  
Author(s):  
Claire Ditchfield ◽  
Victoria L. Johnson ◽  
Anthony Tighe ◽  
Rebecca Ellston ◽  
Carolyn Haworth ◽  
...  
Keyword(s):  
Kinase Activity ◽  
Kinase Inhibitor ◽  
Spindle Checkpoint ◽  
Aurora Kinase ◽  
Multiple Roles ◽  
Aurora B ◽  
Aurora B Kinase ◽  
Checkpoint Proteins ◽  
Anaphase Onset ◽  
Chromosome Alignment

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.

scholarly journals Bub3p Facilitates Spindle Checkpoint Silencing in Fission Yeast

2009 ◽  
Vol 20 (24) ◽  
pp. 5096-5105 ◽  
Author(s):  
Vincent Vanoosthuyse ◽  
John C. Meadows ◽  
Sjaak J.A. van der Sar ◽  
Jonathan B.A. Millar ◽  
Kevin G. Hardwick
Keyword(s):  
Fission Yeast ◽  
Kinase Activity ◽  
Spindle Checkpoint ◽  
Aurora Kinase ◽  
Yeast Cells ◽  
Anaphase Promoting Complex ◽  
Checkpoint Signaling ◽  
Checkpoint Proteins ◽  
Anaphase Onset ◽  
Checkpoint Recovery

Although critical for spindle checkpoint signaling, the role kinetochores play in anaphase promoting complex (APC) inhibition remains unclear. Here we show that spindle checkpoint proteins are severely depleted from unattached kinetochores in fission yeast cells lacking Bub3p. Surprisingly, a robust mitotic arrest is maintained in the majority of bub3Δ cells, yet they die, suggesting that Bub3p is essential for successful checkpoint recovery. During recovery, two defects are observed: (1) cells mis-segregate chromosomes and (2) anaphase onset is significantly delayed. We show that Bub3p is required to activate the APC upon inhibition of Aurora kinase activity in checkpoint-arrested cells, suggesting that Bub3p is required for efficient checkpoint silencing downstream of Aurora kinase. Together, these results suggest that spindle checkpoint signals can be amplified in the nucleoplasm, yet kinetochore localization of spindle checkpoint components is required for proper recovery from a spindle checkpoint-dependent arrest.

scholarly journals CENP-I and Aurora B act as a molecular switch that ties RZZ/Mad1 recruitment to kinetochore attachment status

2014 ◽  
Vol 205 (4) ◽  
pp. 541-554 ◽  
Author(s):  
Daniel R. Matson ◽  
P. Todd Stukenberg
Keyword(s):  
Kinase Activity ◽  
Spindle Checkpoint ◽  
Molecular Switch ◽  
Aurora B ◽  
Aurora B Kinase ◽  
Dynamic Regulation ◽  
Checkpoint Proteins ◽  
Centromere Protein ◽  
Stable Association ◽  
Checkpoint Signal

The RZZ (Rod, ZW10, and Zwilch) complex and Mad1 proteins tightly associate with kinetochores to generate the spindle checkpoint signal, but they are released when a kinetochore forms mature microtubule attachments. Here we demonstrate that the centromere protein CENP-I is required to generate a stable association of RZZ and Mad1 with kinetochores. CENP-I also inhibits their removal by dynein stripping. This regulation of Mad1 and RZZ dissociation functions independently of Aurora B, which regulates their association. We show that the microtubule status of each kinetochore independently dictates the recruitment of Aurora B kinase, kinase activity on a kinetochore substrate, and loading of spindle checkpoint proteins. This dynamic regulation of Mad1 association by Aurora B is only uncovered when CENP-I is depleted, consistent with our finding that CENP-I inhibits the dissociation of Mad1. We conclude that the dual activities of Aurora B and CENP-I generate a molecular switch that maintains a robust spindle checkpoint signal at prometaphase kinetochores until they attain mature attachments to microtubules.

Interplay between mitotic kinesins and the Aurora kinase–PP1 (protein phosphatase 1) axis

2013 ◽  
Vol 41 (6) ◽  
pp. 1761-1765 ◽  
Author(s):  
John C. Meadows
Keyword(s):  
Protein Phosphatase ◽  
Spindle Assembly Checkpoint ◽  
Spindle Checkpoint ◽  
Aurora Kinase ◽  
Protein Phosphatase 1 ◽  
Aurora B ◽  
Spatial Gradient ◽  
Cell Cycle Regulators ◽  
Aurora B Kinase ◽  
Surveillance Mechanism

Correct transmission of genetic information from mother to daughter cells is necessary for development and survival. Accurate segregation is achieved by bipolar attachment of sister kinetochores in each chromatid pair to spindle microtubules emanating from opposite spindle poles, a process known as chromosome bi-orientation. Achieving this requires dynamic interplay between kinetochore proteins, kinesin motor proteins and cell cycle regulators. Chromosome bi-orientation is monitored by a surveillance mechanism known as the SAC (spindle assembly checkpoint). The Aurora B kinase, which is bound to the inner centromere during early mitosis, plays a central role in both chromosome bi-orientation and the spindle checkpoint. The application of tension across centromeres establishes a spatial gradient of high phosphorylation activity at the inner centromere and low phosphorylation activity at the outer kinetochore. This gradient is further refined by the association of PP1 (protein phosphatase 1) to the outer kinetochore, which stabilizes kinetochore–microtubule interactions and silences the spindle checkpoint by dephosphorylating Aurora B kinase targets when chromosome bi-orientation is achieved. In the present review, I discuss emerging evidence that bidirectional cross-talk between mitotic kinesins and the Aurora kinase–PP1 axis is crucial for co-ordinating chromosome bi-orientation and spindle checkpoint signalling in eukaryotes.

scholarly journals Chk2 prevents mitotic exit when the majority of kinetochores are unattached

2014 ◽  
Vol 205 (3) ◽  
pp. 339-356 ◽  
Author(s):  
Eleni Petsalaki ◽  
George Zachos
Keyword(s):  
Spindle Checkpoint ◽  
Mitotic Exit ◽  
Aurora B ◽  
Anaphase Onset ◽  
Chromosome Alignment ◽  
Essential Function ◽  
In Cells

The spindle checkpoint delays exit from mitosis in cells with spindle defects. In this paper, we show that Chk2 is required to delay anaphase onset when microtubules are completely depolymerized but not in the presence of relatively few unattached kinetochores. Mitotic exit in Chk2-deficient cells correlates with reduced levels of Mps1 protein and increased Cdk1–tyrosine 15 inhibitory phosphorylation. Chk2 localizes to kinetochores and is also required for Aurora B–serine 331 phosphorylation in nocodazole or unperturbed early prometaphase. Serine 331 phosphorylation contributed to prometaphase accumulation in nocodazole after partial Mps1 inhibition and was required for spindle checkpoint establishment at the beginning of mitosis. In addition, expression of a phosphomimetic S331E mutant Aurora B rescued chromosome alignment or segregation in Chk2-deficient cells. We propose that Chk2 stabilizes Mps1 and phosphorylates Aurora B–serine 331 to prevent mitotic exit when most kinetochores are unattached. These results highlight mechanisms of an essential function of Chk2 in mitosis.

A phase I, open-label, first-time-in-patient dose escalation and expansion study to assess the safety, tolerability, and pharmacokinetics of nanoparticle encapsulated Aurora B kinase inhibitor AZD2811 in patients with advanced solid tumours.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS2608-TPS2608 ◽  
Author(s):  
Howard A. Burris ◽  
Judy Sing-Zan Wang ◽  
Melissa Lynne Johnson ◽  
Gerald Steven Falchook ◽  
Suzanne Fields Jones ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Kinase Inhibitor ◽  
Subsequent Development ◽  
Aurora Kinase ◽  
Maximum Tolerated Dose ◽  
Aurora B ◽  
Aurora B Kinase ◽  
Open Label ◽  
Aurora Kinase B ◽  
Chemotherapy Study

TPS2608 Background: Aurora kinase B performs key roles in the regulation of the cell cycle and represents a potential target for anticancer therapy. AZD2811, formerly designated AZD1152 hydroxy-quinazoline pyrazole anilide (AZD1152 hQPA), is a potent and selective inhibitor of Aurora B kinase activity and has been incorporated into a polymer nanoparticle carrier for intravenous (IV) administration. The phosphate pro-drug of AZD2811, known as AZD1152 (barasertib), reached Phase II of clinical development as a continuous IV infusion. While promising efficacy was seen with barasertib in elderly acute myeloid leukaemia (AML) patients ( Kantarjian HG et al., Cancer 2013;119:2611-19), continuous intravenous drug delivery precluded subsequent development in this disease setting and there were limited clinical responses in solid tumour patients due to dose-limiting myelotoxicity. AZD2811 nanoparticle has been designed to overcome these issues. Methods: Patients with relapsed advanced solid malignancies with no standard treatments are eligible for the part A dose escalation. Primary endpoint is to determine the maximum tolerated dose of AZD2811 nanoparticle using a 3+3 design. Patients with refractory/relapsed small cell lung cancer (SCLC) will be eligible for the part B expansion, where the safety, PK and anti-tumour activity of AZD2811 nanoparticle will be assessed as monotherapy and in combination with chemotherapy. Study enrolment is ongoing. Clinical trial information: NCT02579226.

scholarly journals Bub3 and Bub1 maintain the balance of kinetochore-localized Aurora B Kinase and Protein Phosphatase I to Regulate Chromosome Segregation and Anaphase Onset in Meiosis

2019 ◽  
Author(s):  
Gisela Cairo ◽  
Anne M. MacKenzie ◽  
Soni Lacefield
Keyword(s):  
Chromosome Segregation ◽  
Protein Phosphatase ◽  
Meiotic Chromosome ◽  
Protein Phosphatase 1 ◽  
Aurora B ◽  
Aurora B Kinase ◽  
Checkpoint Proteins ◽  
Anaphase Onset ◽  
Normal Duration ◽  
Spindle Microtubules

AbstractAccurate chromosome segregation depends on proper attachment of kinetochores to spindle microtubules prior to anaphase onset. The Ipl1/Aurora B kinase corrects improper attachments by phosphorylating kinetochore components and so releasing aberrant kinetochore-microtubule interactions. The localization of Ipl1 to kinetochores in budding yeast depends upon multiple pathways, including the Bub1/Bub3 pathway. We show here that in meiosis, Bub3 is crucial for correction of attachment errors. Depletion of Bub3 results in reduced levels of kinetochore-localized Ipl1, and concomitant massive chromosome mis-segregation caused by incorrect chromosome-spindle attachments. Depletion of Bub3 also results in shorter metaphase I and metaphase II due to premature localization of protein phosphatase 1 (PP1) to kinetochores, which antagonizes Ipl1-mediated phosphorylation. We propose a new role for the Bub1-Bub3 pathway in maintaining the balance between kinetochore-localization of Ipl1 and PP1, a balance that is essential for accurate meiotic chromosome segregation and timely anaphase onset.SummaryCairo et al show that in S. cerevisiae meiosis, spindle checkpoint proteins Bub1 and Bub3 have an essential role in preventing chromosome mis-segregation and setting the normal duration of anaphase I and anaphase II onset by regulating the kinetochore-localization of Ipl1 and PP1.

scholarly journals KNL1 facilitates phosphorylation of outer kinetochore proteins by promoting Aurora B kinase activity

2013 ◽  
Vol 203 (6) ◽  
pp. 957-969 ◽  
Author(s):  
Gina V. Caldas ◽  
Keith F. DeLuca ◽  
Jennifer G. DeLuca
Keyword(s):  
Kinase Activity ◽  
Aurora B ◽  
Wild Type ◽  
Aurora B Kinase ◽  
Kinetochore Protein ◽  
Anaphase Onset ◽  
N Terminus ◽  
Late Mitosis ◽  
Early Mitosis

Aurora B kinase phosphorylates kinetochore proteins during early mitosis, increasing kinetochore–microtubule (MT) turnover and preventing premature stabilization of kinetochore–MT attachments. Phosphorylation of kinetochore proteins during late mitosis is low, promoting attachment stabilization, which is required for anaphase onset. The kinetochore protein KNL1 recruits Aurora B–counteracting phosphatases and the Aurora B–targeting factor Bub1, yet the consequences of KNL1 depletion on Aurora B phospho-regulation remain unknown. Here, we demonstrate that the KNL1 N terminus is essential for Aurora B activity at kinetochores. This region of KNL1 is also required for Bub1 kinase activity at kinetochores, suggesting that KNL1 promotes Aurora B activity through Bub1-mediated Aurora B targeting. However, ectopic targeting of Aurora B to kinetochores does not fully rescue Aurora B activity in KNL1-depleted cells, suggesting KNL1 influences Aurora B activity through an additional pathway. Our findings establish KNL1 as a requirement for Aurora B activity at kinetochores and for wild-type kinetochore–MT attachment dynamics.

scholarly journals Regulation of Kinetochore Recruitment of Two Essential Mitotic Spindle Checkpoint Proteins by Mps1 Phosphorylation

2009 ◽  
Vol 20 (1) ◽  
pp. 10-20 ◽  
Author(s):  
Quanbin Xu ◽  
Songcheng Zhu ◽  
Wei Wang ◽  
Xiaojuan Zhang ◽  
William Old ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Mitotic Spindle ◽  
Kinase Activity ◽  
Spindle Checkpoint ◽  
Signaling Cascade ◽  
Checkpoint Activation ◽  
Mitotic Spindle Checkpoint ◽  
Checkpoint Signaling ◽  
Checkpoint Proteins ◽  
Anaphase Onset

Mps1 is a protein kinase that plays essential roles in spindle checkpoint signaling. Unattached kinetochores or lack of tension triggers recruitment of several key spindle checkpoint proteins to the kinetochore, which delays anaphase onset until proper attachment or tension is reestablished. Mps1 acts upstream in the spindle checkpoint signaling cascade, and kinetochore targeting of Mps1 is required for subsequent recruitment of Mad1 and Mad2 to the kinetochore. The mechanisms that govern recruitment of Mps1 or other checkpoint proteins to the kinetochore upon spindle checkpoint activation are incompletely understood. Here, we demonstrate that phosphorylation of Mps1 at T12 and S15 is required for Mps1 recruitment to the kinetochore. Mps1 kinetochore recruitment requires its kinase activity and autophosphorylation at T12 and S15. Mutation of T12 and S15 severely impairs its kinetochore association and markedly reduces recruitment of Mad2 to the kinetochore. Our studies underscore the importance of Mps1 autophosphorylation in kinetochore targeting and spindle checkpoint signaling.

scholarly journals Enhancement of radiation response in p53-deficient cancer cells by the Aurora-B kinase inhibitor AZD1152

Oncogene ◽  
2007 ◽  
Vol 27 (23) ◽  
pp. 3244-3255 ◽  
Author(s):  
Y Tao ◽  
P Zhang ◽  
F Girdler ◽  
V Frascogna ◽  
M Castedo ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Kinase Inhibitor ◽  
Radiation Response ◽  
Aurora B ◽  
Aurora B Kinase

scholarly journals Cytoplasmic dynein participates in meiotic checkpoint inactivation in mouse oocytes by transporting cytoplasmic mitotic arrest-deficient (Mad) proteins from kinetochores to spindle poles

Reproduction ◽  
2007 ◽  
Vol 133 (4) ◽  
pp. 685-695 ◽  
Author(s):  
Dong Zhang ◽  
Shen Yin ◽  
Man-Xi Jiang ◽  
Wei Ma ◽  
Yi Hou ◽  
...  
Keyword(s):  
Spindle Checkpoint ◽  
Germinal Vesicle ◽  
Cytoplasmic Dynein ◽  
Mitotic Arrest ◽  
Checkpoint Proteins ◽  
Meiotic Progression ◽  
Spindle Poles ◽  
Anaphase Onset ◽  
Oocyte Meiosis ◽  
And Function

The present study was designed to investigate the localization and function of cytoplasmic dynein (dynein) during mouse oocyte meiosis and its relationship with two major spindle checkpoint proteins, mitotic arrest-deficient (Mad) 1 and Mad2. Oocytes at various stages during the first meiosis were fixed and immunostained for dynein, Mad1, Mad2, kinetochores, microtubules, and chromosomes. Some oocytes were treated with nocodazole before examination. Anti-dynein antibody was injected into the oocytes at germinal vesicle (GV) stage before the examination of its effects on meiotic progression or Mad1 and Mad2 localization. Results showed that dynein was present in the oocytes at various stages from GV to metaphase II and the locations of Mad1 and Mad2 were associated with dynein’s movement. Both Mad1 and Mad2 had two existing states: one existed in the cytoplasm (cytoplasmic Mad1 or cytoplasmic Mad2), which did not bind to kinetochores, while the other bound to kinetochores (kinetochore Mad1 or kinetochore Mad2). The equilibrium between the two states varied during meiosis and/or in response to the changes of the connection between microtubules and kinetochores. Cytoplasmic Mad1 and Mad2 recruited to chromosomes when the connection between microtubules and chromosomes was destroyed. Inhibition of dynein interferes with cytoplasmic Mad1 and Mad2 transportation from chromosomes to spindle poles, thus inhibits checkpoint silence and delays anaphase onset. These results indicate that dynein may play a role in spindle checkpoint inactivation.

Sign in / Sign up

Export Citation Format

Share Document