Roles of Aurora Kinases in Mitosis and Tumorigenesis

Fu, Jingyan; Bian, Minglei; Jiang, Qing; Zhang, Chuanmao

doi:10.1158/1541-7786.mcr-06-0208

Cited by 534 publications

(530 citation statements)

References 115 publications

(154 reference statements)

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“…Among the genes inhibited were those involved in the aurora B kinase and polo-like kinase pathways, which are important for cell cycle processes, such as spindle formation, DNA replication, and cytokinesis (27,28). When the transcriptome of CD41 T cells from abatacept-treated mice was compared with that of the cells from naive mice, it was clear that many gene sets relating to TCR signaling were induced in the former mouse group, including Cd3d, Lck, and Zap70 (data available upon request from the corresponding author).…”

Section: Effect Of Abatacept On T Cells and Apcs During Primary Immunmentioning

confidence: 99%

Abatacept Inhibition of T Cell Priming in Mice by Induction of a Unique Transcriptional Profile That Reduces Their Ability to Activate Antigen‐Presenting Cells

Patakas

Weir

et al. 2016

Arthritis & Rheumatology

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Objective. To determine at the phenotypic, functional, and transcriptional levels whether abatacept, a CTLA-4Ig molecule that binds with high affinity to CD80/86 on antigen-presenting cells (APCs) and is used to treat rheumatoid arthritis, induces a state of immunologic tolerance in T cells and dendritic cells in mice.Methods. We investigated the capacity of abatacept to regulate the development of antigen-specific immunologic tolerance in vivo using murine models of priming and tolerance to generate highly purified antigen-specific T cell populations and CD11c1 APCs. These were combined with detailed immunologic and full genome transcriptional analyses.Results. We found that abatacept inhibited T cell activation, but did not render T cells anergic or lead to the generation of Treg cells. However, it induced a sustained inhibition of T cell activation due to the inability of these cells to progress through the cell cycle following T cell receptor stimulation. We also observed that this state was accompanied by an inhibition of dendritic cell activation due to their reduced licensing by T cells.Conclusion. This study provides detailed insight into the mode of action of abatacept, demonstrating that its effectiveness is not due to the induction of T cell tolerance, but rather to a sustained inhibition of T cell activation that results in reduced functionality of APCs, with significant implications for its clinical application.

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Section: Effect Of Abatacept On T Cells and Apcs During Primary Immunmentioning

confidence: 99%

Abatacept Inhibition of T Cell Priming in Mice by Induction of a Unique Transcriptional Profile That Reduces Their Ability to Activate Antigen‐Presenting Cells

Patakas

Weir

et al. 2016

Arthritis & Rheumatology

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“…Aberrations in genetic pathways controlling cell cycle cause abnormal cell growth, senescence, and apoptosis, inducing malignant transformation of cells [6,7]. Aurora kinases are a novel family of mitotic serine/threonine kinases involved in different processes of cell cycle control [8]. Aurora kinase A (AURKA), whose expression is cell cycle dependent, is mainly involved in centrosome maturation, spindle assembly, and chromosome segregation, and it is associated with several co-activators such as BORA, TPX2, Ajuba (JUB), TACC1, and GADD45a that drive the localization, activation, and substrate preference during cell division [9,10].…”

Section: Introductionmentioning

confidence: 99%

HIF-1 is involved in the negative regulation of AURKA expression in breast cancer cell lines under hypoxic conditions

Fanale

Bazan

Corsini

et al. 2013

Breast Cancer Res Treat

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Numerous microarray-based gene expression studies performed on several types of solid tumors revealed significant changes in key genes involved in progression and regulation of the cell cycle, including AURKA that is known to be overexpressed in many types of human malignancies. Tumor hypoxia is associated with poor prognosis in several cancer types, including breast cancer (BC). Since hypoxia is a condition that influences the expression of many genes involved in tumorigenesis, proliferation, and cell cycle regulation, we performed a microarray-based gene expression analysis in order to identify differentially expressed genes in BC cell lines exposed to hypoxia. This analysis showed that hypoxia induces a down-regulation of AURKA expression. Although hypoxia is a tumor feature, the molecular mechanisms that regulate AURKA expression in response to hypoxia in BC are still unknown. For the first time, we demonstrated that HIF-1 activation downstream of hypoxia could drive AURKA down-regulation in BC cells. In fact, we found that siRNA-mediated knockdown of HIF-1a significantly reduces the AURKA down-regulation in BC cells under hypoxia. The aim of our study was to obtain new insights into AURKA transcriptional regulation in hypoxic conditions. Luciferase reporter assays showed a reduction of AURKA promoter activity in hypoxia. Unlike the previous findings, we hypothesize a new possible mechanism where HIF-1, rather than inducing transcriptional activation, could promote the AURKA down-regulation via its binding to hypoxia-responsive elements into the proximal region of the AURKA promoter. The present study shows that hypoxia directly links HIF-1 with AURKA expression, suggesting a possible pathophysiological role of this new pathway in BC and confirming HIF-1 as an important player linking an environmental signal to the AURKA promoter. Since AURKA down-regulation overrides the estrogen-mediated growth and chemoresistance in BC cells, these findings could be important for the development of new possible therapies against BC.

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“…The aurora kinase family includes genes Aurora A, Aurora B, and Aurora C. Of these, Aurora B kinase (AURKB) is a multi-functional chromosomal passenger protein, localized on the centromeres from prophase through the metaphase-anaphase transition. 5 Analysis of prostate patient samples revealed overexpression of AURKB in androgen-independent cancers rather than androgen-dependent cancers. 6 Furthermore, AURKB-transfected cells have an unstable chromosome number and show aggressive tumor phenotype.…”

Section: Introductionmentioning

confidence: 99%

RNAi-mediated knockdown of AURKB and EGFR shows enhanced therapeutic efficacy in prostate tumor regression

et al. 2009

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Aurora B kinase (AURKB) and epidermal growth factor receptor 1 (EGFR) belong to serine/threonine and tyrosine kinase family of proteins. Both these kinases are found to overexpress in a large number of epithelial cancers, including hormonal refractory prostate cancer. In this communication, we present evidence for down-regulated expression of AURKB and EGFR, either alone or in combination, in prostate cancer cells. The results show that AURKB and EGFR were efficiently down-regulated in a dose-dependent manner. AURKB and EGFR siRNA in combination have shown enhanced therapeutic effect by inhibiting PC3 cell proliferation and inducing apoptosis in vitro, whereas androgen-dependent cancer cells LNCaP remain unaffected correlating the endogenous expression levels. Knockdown of AURKB and EGFR individually resulted in inhibition of prostate tumor growth in athymic nude mice and their combined knockdown resulted in tumor regression in which 40% of the treated mice were found to be tumor free, implicating the potential therapeutic benefits of AURKB-EGFR combination therapy.

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Roles of Aurora Kinases in Mitosis and Tumorigenesis

Cited by 534 publications

References 115 publications

Abatacept Inhibition of T Cell Priming in Mice by Induction of a Unique Transcriptional Profile That Reduces Their Ability to Activate Antigen‐Presenting Cells

Abatacept Inhibition of T Cell Priming in Mice by Induction of a Unique Transcriptional Profile That Reduces Their Ability to Activate Antigen‐Presenting Cells

HIF-1 is involved in the negative regulation of AURKA expression in breast cancer cell lines under hypoxic conditions

RNAi-mediated knockdown of AURKB and EGFR shows enhanced therapeutic efficacy in prostate tumor regression

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