Mitotic requirement for aurora A kinase is bypassed in the absence of aurora B kinase

FEBS Letters ◽  
2005 ◽  
Vol 579 (16) ◽  
pp. 3385-3391 ◽  
Author(s):  
Hui Yang ◽  
Teresa Burke ◽  
Jack Dempsey ◽  
Bruce Diaz ◽  
Elizabeth Collins ◽  
...  
Keyword(s):  
Aurora B ◽  
Aurora A Kinase ◽  
Aurora A ◽  
Aurora B Kinase

scholarly journals VX-680 Inhibits Aurora A and Aurora B Kinase Activity in Human Cells

Cell Cycle ◽  
2007 ◽  
Vol 6 (22) ◽  
pp. 2846-2854 ◽  
Author(s):  
Rebecca K. Tyler ◽  
Natalia Shpiro ◽  
Rodolfo Marquez ◽  
Patrick A. Eyers
Keyword(s):  
Kinase Activity ◽  
Human Cells ◽  
Aurora B ◽  
Aurora A ◽  
Aurora B Kinase

scholarly journals Aurora A kinase phosphorylates Hec1 to regulate metaphase kinetochore–microtubule dynamics

2017 ◽  
Vol 217 (1) ◽  
pp. 163-177 ◽  
Author(s):  
Keith F. DeLuca ◽  
Amanda Meppelink ◽  
Amanda J. Broad ◽  
Jeanne E. Mick ◽  
Olve B. Peersen ◽  
...  
Keyword(s):  
Chromosome Segregation ◽  
Microtubule Dynamics ◽  
Aurora B ◽  
Aurora A Kinase ◽  
Aurora A ◽  
Tail Domain ◽  
Mitotic Chromosomes ◽  
Metaphase Chromosomes ◽  
Mitotic Kinases ◽  
Microtubule Attachment

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.

Megakaryocytes express functional Aurora-B kinase in endomitosis

Blood ◽  
2004 ◽  
Vol 104 (4) ◽  
pp. 1017-1024 ◽  
Author(s):  
Amy E. Geddis ◽  
Kenneth Kaushansky
Keyword(s):  
Aurora Kinase ◽  
Aurora B ◽  
Aurora A Kinase ◽  
Aurora B Kinase ◽  
Late Anaphase ◽  
Chromosomal Passenger ◽  
Early Anaphase ◽  
Chromosomal Passenger Proteins ◽  
Diploid Cells ◽  
Passenger Proteins

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.

scholarly journals Phase II Intergroup Trial of Alisertib in Relapsed and Refractory Peripheral T-Cell Lymphoma and Transformed Mycosis Fungoides: SWOG 1108

2015 ◽  
Vol 33 (21) ◽  
pp. 2399-2404 ◽  
Author(s):  
Paul M. Barr ◽  
Hongli Li ◽  
Catherine Spier ◽  
Daruka Mahadevan ◽  
Michael LeBlanc ◽  
...  
Keyword(s):  
T Cell ◽  
Mycosis Fungoides ◽  
Phase Ii ◽  
Cell Lymphoma ◽  
Large Cell ◽  
T Cell Lymphoma ◽  
Phase Iii ◽  
Aurora B ◽  
Aurora A Kinase ◽  
Aurora B Kinase

Purpose Aurora A kinase (AAK) is upregulated in highly proliferative lymphomas, suggesting its potential as a therapeutic target. Alisertib is a novel oral AAK inhibitor without adverse safety signals in early-phase studies that demonstrated preliminary activity in T-cell lymphoma. This phase II study was conducted to further investigate the efficacy of alisertib in relapsed or refractory peripheral T-cell non-Hodgkin lymphoma (PTCL). Patients and Methods Eligible patients with histologically confirmed relapsed/refractory PTCL or transformed Mycosis fungoides (tMF) received alisertib 50 mg twice a day for 7 days on 21-day cycles. Results Of 37 eligible patients, the histologic subtypes enrolled included PTCL not otherwise specified (n = 13), angioimmunoblastic T-cell lymphoma (n = 9), tMF (n = 7), adult T-cell lymphoma/leukemia (n = 4), anaplastic large-cell lymphoma (n = 2), and extranodal natural killer/T-cell lymphoma (n = 2). Grade 3 and 4 adverse events in ≥ 5% of patients included neutropenia (32%), anemia (30%), thrombocytopenia (24%), febrile neutropenia (14%), mucositis (11%), and rash (5%). Treatment was discontinued most commonly for disease progression. Among the PTCL subtypes, the overall response rate was 30%, whereas no responses were observed in tMF. Aurora B kinase was more commonly overexpressed than AAK in tumor specimens. Analysis of AAK, Aurora B kinase, MYC, BCL-2, phosphatidylinositol 3-kinase γ, and Notch1 expression revealed no association with response. Conclusion Alisertib has antitumor activity in PTCL, including heavily pretreated patients. These promising results are being further investigated in an ongoing international, randomized phase III trial comparing alisertib with investigator's choice in PTCL.

scholarly journals Mitotic Phosphorylation of Histone H3: Spatio-Temporal Regulation by Mammalian Aurora Kinases

2002 ◽  
Vol 22 (3) ◽  
pp. 874-885 ◽  
Author(s):  
Claudia Crosio ◽  
Gian Maria Fimia ◽  
Romain Loury ◽  
Masashi Kimura ◽  
Yukio Okano ◽  
...  
Keyword(s):  
Cell Transformation ◽  
Histone H3 ◽  
Aurora B ◽  
Chromosome Loss ◽  
Aurora A Kinase ◽  
Aurora A ◽  
H3 Phosphorylation ◽  
Spatio Temporal

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.

scholarly journals Aurora A and Aurora B jointly coordinate chromosome segregation and anaphase microtubule dynamics

2011 ◽  
Vol 195 (7) ◽  
pp. 1103-1113 ◽  
Author(s):  
Nadia Hégarat ◽  
Ewan Smith ◽  
Gowri Nayak ◽  
Shunichi Takeda ◽  
Patrick A. Eyers ◽  
...  
Keyword(s):  
Chromosome Segregation ◽  
Aurora B ◽  
Aurora A Kinase ◽  
Aurora A ◽  
Daughter Cells ◽  
Conditional Deletion ◽  
Alignment Problem ◽  
Single Nucleus ◽  
Bipolar Spindles ◽  
Dt40 Cells

We established a conditional deletion of Aurora A kinase (AurA) in Cdk1 analogue-sensitive DT40 cells to analyze AurA knockout phenotypes after Cdk1 activation. In the absence of AurA, cells form bipolar spindles but fail to properly align their chromosomes and exit mitosis with segregation errors. The resulting daughter cells exhibit a variety of phenotypes and are highly aneuploid. Aurora B kinase (AurB)–inhibited cells show a similar chromosome alignment problem and cytokinesis defects, resulting in binucleate daughter cells. Conversely, cells lacking AurA and AurB activity exit mitosis without anaphase, forming polyploid daughter cells with a single nucleus. Strikingly, inhibition of both AurA and AurB results in a failure to depolymerize spindle microtubules (MTs) in anaphase after Cdk1 inactivation. These results suggest an essential combined function of AurA and AurB in chromosome segregation and anaphase MT dynamics.

Centrosome Aurora A gradient ensures single polarity axis in C. elegans embryos

2020 ◽  
Vol 48 (3) ◽  
pp. 1243-1253 ◽  
Author(s):  
Sukriti Kapoor ◽  
Sachin Kotak
Keyword(s):  
Symmetry Breaking ◽  
Cell Fate ◽  
Cell Cortex ◽  
Axis Formation ◽  
Aurora A Kinase ◽  
Aurora A ◽  
C Elegans ◽  
Cell Embryo ◽  
Polarity Establishment

Cellular asymmetries are vital for generating cell fate diversity during development and in stem cells. In the newly fertilized Caenorhabditis elegans embryo, centrosomes are responsible for polarity establishment, i.e. anterior–posterior body axis formation. The signal for polarity originates from the centrosomes and is transmitted to the cell cortex, where it disassembles the actomyosin network. This event leads to symmetry breaking and the establishment of distinct domains of evolutionarily conserved PAR proteins. However, the identity of an essential component that localizes to the centrosomes and promotes symmetry breaking was unknown. Recent work has uncovered that the loss of Aurora A kinase (AIR-1 in C. elegans and hereafter referred to as Aurora A) in the one-cell embryo disrupts stereotypical actomyosin-based cortical flows that occur at the time of polarity establishment. This misregulation of actomyosin flow dynamics results in the occurrence of two polarity axes. Notably, the role of Aurora A in ensuring a single polarity axis is independent of its well-established function in centrosome maturation. The mechanism by which Aurora A directs symmetry breaking is likely through direct regulation of Rho-dependent contractility. In this mini-review, we will discuss the unconventional role of Aurora A kinase in polarity establishment in C. elegans embryos and propose a refined model of centrosome-dependent symmetry breaking.

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