Aurora A kinase (AURKA) in normal and pathological cell division.
TL;DR: The mitotic and non-mitotic functions of Aurora A are reviewed, Aurora A regulation in the context of protein structural information is discussed, and progress in understanding and inhibiting Aurora A in cancer is evaluated.
Abstract: Temporally and spatially controlled activation of the Aurora A kinase (AURKA) regulates centrosome maturation, entry into mitosis, formation and function of the bipolar spindle, and cytokinesis. Genetic amplification and mRNA and protein overexpression of Aurora A are common in many types of solid tumor, and associated with aneuploidy, supernumerary centrosomes, defective mitotic spindles, and resistance to apoptosis. These properties have led Aurora A to be considered a high-value target for development of cancer therapeutics, with multiple agents currently in early-phase clinical trials. More recently, identification of additional, non-mitotic functions and means of activation of Aurora A during interphase neurite elongation and ciliary resorption have significantly expanded our understanding of its function, and may offer insights into the clinical performance of Aurora A inhibitors. Here we review the mitotic and non-mitotic functions of Aurora A, discuss Aurora A regulation in the context of protein structural information, and evaluate progress in understanding and inhibiting Aurora A in cancer.
Citations
More filters
TL;DR: How cell adhesions interact with nanotopography is discussed, and insight is provided as to how materials scientists can exploit these interactions to direct stem cell fate and to understand how the behaviour of stem cells in their niche can be controlled.
Abstract: Stem cells respond to nanoscale surface features, with changes in cell growth and differentiation mediated by alterations in cell adhesion. The interaction of nanotopographical features with integrin receptors in the cells' focal adhesions alters how the cells adhere to materials surfaces, and defines cell fate through changes in both cell biochemistry and cell morphology. In this Review, we discuss how cell adhesions interact with nanotopography, and we provide insight as to how materials scientists can exploit these interactions to direct stem cell fate and to understand how the behaviour of stem cells in their niche can be controlled. We expect knowledge gained from the study of cell-nanotopography interactions to accelerate the development of next-generation stem cell culture materials and implant interfaces, and to fuel discovery of stem cell therapeutics to support regenerative therapies.
879 citations
Cites background from "Aurora A kinase (AURKA) in normal a..."
...adhesions [57, 86], and the cytoskeleton [126] have been suggested....
[...]
TL;DR: Progress made in uncovering aspects of the biology of SCLC and its microenvironment that are defining new therapeutic strategies and offering renewed hope for patients are reviewed.
Abstract: Small-cell lung cancer (SCLC) is an aggressive malignancy associated with a poor prognosis First-line treatment has remained unchanged for decades, and a paucity of effective treatment options exists for recurrent disease Nonetheless, advances in our understanding of SCLC biology have led to the development of novel experimental therapies Poly [ADP-ribose] polymerase (PARP) inhibitors have shown promise in preclinical models, and are under clinical investigation in combination with cytotoxic therapies and inhibitors of cell-cycle checkpointsPreclinical data indicate that targeting of histone-lysine N-methyltransferase EZH2, a regulator of chromatin remodelling implicated in acquired therapeutic resistance, might augment and prolong chemotherapy responses High expression of the inhibitory Notch ligand Delta-like protein 3 (DLL3) in most SCLCs has been linked to expression of Achaete-scute homologue 1 (ASCL1; also known as ASH-1), a key transcription factor driving SCLC oncogenesis; encouraging preclinical and clinical activity has been demonstrated for an anti-DLL3-antibody-drug conjugate The immune microenvironment of SCLC seems to be distinct from that of other solid tumours, with few tumour-infiltrating lymphocytes and low levels of the immune-checkpoint protein programmed cell death 1 ligand 1 (PD-L1) Nonetheless, immunotherapy with immune-checkpoint inhibitors holds promise for patients with this disease, independent of PD-L1 status Herein, we review the progress made in uncovering aspects of the biology of SCLC and its microenvironment that are defining new therapeutic strategies and offering renewed hope for patients
302 citations
TL;DR: In this article, the authors examined the significance of this heterogeneity and identified a unique motif in PSEN2 that directs this γ-secretase to late endosomes/lysosomes via a phosphorylationdependent interaction with the AP-1 adaptor complex.
223 citations
Cites background from "Aurora A kinase (AURKA) in normal a..."
...Although Aurora A is predominantly known for its role in cell-cycle regulation and mitosis (Nikonova et al., 2013), this kinase has recently been linked to other functions, such as neurite outgrowth (Takitoh et al., 2012) and mitochondria-associated ER membrane control E/LYS....
[...]
...Although Aurora A is predominantly known for its role in cell-cycle regulation and mitosis (Nikonova et al., 2013), this kinase has recently been linked to other functions, such as neurite outgrowth (Takitoh et al....
[...]
TL;DR: These data support further clinical assessment of alisertib in patients with solid tumours, particularly those with breast cancer and small-cell lung cancer.
Abstract: Summary Background Alisertib is an investigational, oral, selective inhibitor of aurora kinase A. We aimed to investigate the safety and activity of single-agent alisertib in patients with predefined types of advanced solid tumours. Methods We did a multicentre phase 1/2 study at 40 centres in four countries (Czech Republic, France, Poland, and the USA). Here, we report results from phase 2; enrolment for the study began on Feb 16, 2010, and ended on May 3, 2013. Adult patients were eligible for the study if they had either breast cancer, small-cell lung cancer, non-small-cell lung cancer, head and neck squamous-cell carcinoma, or gastro-oesophageal adenocarcinoma that had relapsed or was refractory to chemotherapy. Patients had to have undergone two or fewer previous cytotoxic regimens (four or fewer for breast cancer patients), not including adjuvant or neoadjuvant treatments. Enrolment followed a two-stage design: to proceed to the second stage, two or more objective responses were needed in the first 20 response-assessable patients in each of the five tumour cohorts. Alisertib was administered orally in 21-day cycles at the recommended phase 2 dose of 50 mg twice daily for 7 days followed by a break of 14 days. The protocol-specified primary endpoint was the proportion of patients with an objective response, assessed by Response Evaluation Criteria In Solid Tumors version 1.1 in the response-assessable population (ie, patients with measurable disease who received at least one dose of alisertib and had undergone at least one post-baseline tumour assessment). This completed trial is registered with ClinicalTrials.gov, NCT01045421. Findings By May 31, 2013, 249 patients had been treated, 53 with breast cancer, 60 with small-cell lung cancer, 26 with non-small-cell lung cancer, 55 with head and neck squamous-cell carcinoma, and 55 with gastro-oesophageal adenocarcinoma. Among response-assessable patients, an objective response was noted in nine (18%, 95% CI 9−32) of 49 women with breast cancer, ten (21%, 10−35) of 48 participants with small-cell lung cancer, one (4%, 0−22) of 23 patients with non-small-cell lung cancer, four (9%, 2−21) of 45 people with head and neck squamous-cell carcinoma, and four (9%, 2−20) of 47 individuals with gastro-oesophageal adenocarcinoma; all were partial responses. Adverse events were similar across tumour types. The most frequent drug-related grade 3–4 adverse events included neutropenia (n=107 [43%]), leukopenia (53 [21%]), and anaemia (26 [10%]). Serious drug-related adverse events were reported in 108 (43%) patients. Interpretation These data support further clinical assessment of alisertib in patients with solid tumours, particularly those with breast cancer and small-cell lung cancer. Funding Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.
197 citations
TL;DR: Clinically defined AVPC share molecular features with SCPC and are characterized by combined alterations in RB1, Tp53, and/or PTEN, which was the strongest discriminator between unselected castration-resistant prostate cancer (CRPC) and the AVPC.
Abstract: Purpose: Morphologically heterogeneous prostate cancers that behave clinically like small-cell prostate cancers (SCPC) share their chemotherapy responsiveness. We asked whether these clinically defined, morphologically diverse, “aggressive variant prostate cancer (AVPC)” also share molecular features with SCPC. Experimental Design: Fifty-nine prostate cancer samples from 40 clinical trial participants meeting AVPC criteria, and 8 patient-tumor derived xenografts (PDX) from 6 of them, were stained for markers aberrantly expressed in SCPC. DNA from 36 and 8 PDX was analyzed by Oncoscan for copy number gains (CNG) and losses (CNL). We used the AVPC PDX to expand observations and referenced publicly available datasets to arrive at a candidate molecular signature for the AVPC. Results: Irrespective of morphology, Ki67 and Tp53 stained ≥10% cells in 80% and 41% of samples, respectively. RB1 stained MYC (surrogate for 8q) CNG and RB1 CNL showed in 54% of 44 samples each and PTEN CNL in 48%. All but 1 of 8 PDX bore Tp53 missense mutations. RB1 CNL was the strongest discriminator between unselected castration-resistant prostate cancer (CRPC) and the AVPC. Combined alterations in RB1 , Tp53 , and/or PTEN were more frequent in the AVPC than in unselected CRPC and in The Cancer Genome Atlas samples. Conclusions: Clinically defined AVPC share molecular features with SCPC and are characterized by combined alterations in RB1 , Tp53 , and/or PTEN . Clin Cancer Res; 22(6); 1520–30. ©2015 AACR .
182 citations
Cites background from "Aurora A kinase (AURKA) in normal a..."
...First, amplification of AURKA is most often regional and thus accompanied by the enhanced expression of multiple additional genes, making the attribution of outcomes to AURKA overexpression alone difficult (37)....
[...]
...Indeed, the interactome of AURKA is large (37) and includes cell cycle and transcriptional regulators such as AR (38), Tp53 (39), MYC (40), and BRCA1 (41)....
[...]
...Second, there is a lack of a standard IHC methodology and of a consensus as to what constitutes abnormal AURKA expression (37, 44)....
[...]
References
More filters
[...]
TL;DR: Version 2.8 introduces two powerful new features—Custom Node Graphics and Attribute Equations—which can be used jointly to greatly enhance Cytoscape's data integration and visualization capabilities.
Abstract: Summary: Cytoscape is a popular bioinformatics package for biological network visualization and data integration. Version 2.8 introduces two powerful new features—Custom Node Graphics and Attribute Equations—which can be used jointly to greatly enhance Cytoscape's data integration and visualization capabilities. Custom Node Graphics allow an image to be projected onto a node, including images generated dynamically or at remote locations. Attribute Equations provide Cytoscape with spreadsheet-like functionality in which the value of an attribute is computed dynamically as a function of other attributes and network properties.
Availability and implementation: Cytoscape is a desktop Java application released under the Library Gnu Public License (LGPL). Binary install bundles and source code for Cytoscape 2.8 are available for download from http://cytoscape.org.
Contact: [email protected]
4,186 citations
"Aurora A kinase (AURKA) in normal a..." refers methods in this paper
...Data were imported, merged, and visualized in Cytoscape [252]....
[...]
...Data were imported, merged, and visualized in Cytoscape [252]....
[...]
TL;DR: An update on the online database resource Search Tool for the Retrieval of Interacting Genes (STRING), which provides uniquely comprehensive coverage and ease of access to both experimental as well as predicted interaction information.
Abstract: An essential prerequisite for any systems-level understanding of cellular functions is to correctly uncover and annotate all functional interactions among proteins in the cell. Toward this goal, remarkable progress has been made in recent years, both in terms of experimental measurements and computational prediction techniques. However, public efforts to collect and present protein interaction information have struggled to keep up with the pace of interaction discovery, partly because protein-protein interaction information can be error-prone and require considerable effort to annotate. Here, we present an update on the online database resource Search Tool for the Retrieval of Interacting Genes (STRING); it provides uniquely comprehensive coverage and ease of access to both experimental as well as predicted interaction information. Interactions in STRING are provided with a confidence score, and accessory information such as protein domains and 3D structures is made available, all within a stable and consistent identifier space. New features in STRING include an interactive network viewer that can cluster networks on demand, updated on-screen previews of structural information including homology models, extensive data updates and strongly improved connectivity and integration with third-party resources. Version 9.0 of STRING covers more than 1100 completely sequenced organisms; the resource can be reached at http://string-db.org.
3,239 citations
"Aurora A kinase (AURKA) in normal a..." refers methods in this paper
...Interaction data were collected using online databases String [251] (using medium confidence score 0....
[...]
...Interaction data were collected using online databases String [251] (using medium confidence score 0.4 and excluding text-mining-only results) and Ingenuity [http://www.ingenuity.com/] (extracting only experimental and high confidence predicted interactions)....
[...]
TL;DR: It is reported that STK15 (also known as BTAK and aurora2), encoding a centrosome-associated kinase, is amplified and overexpressed in multiple human tumour cell types, and is involved in the induction of centrosomes duplication-distribution abnormalities and aneuploidy in mammalian cells.
Abstract: The centrosomes are thought to maintain genomic stability through the establishment of bipolar spindles during cell division, ensuring equal segregation of replicated chromosomes to two daughter cells. Deregulated duplication and distribution of centrosomes have been implicated in chromosome segregation abnormalities, leading to aneuploidy seen in many cancer cell types. Here, we report that STK15
(also known as BTAK
and aurora2
), encoding a centrosome-associated kinase, is amplified and overexpressed in multiple human tumour cell types, and is involved in the induction of centrosome duplication-distribution abnormalities and aneuploidy in mammalian cells. STK15
amplification has been previously detected in breast tumour cell lines
1
and in colon tumours
2
; here, we report its amplification in approximately 12% of primary breast tumours, as well as in breast, ovarian, colon, prostate, neuroblastoma and cervical cancer cell lines. Additionally, high expression of STK15
mRNA was detected in tumour cell lines without evidence of gene amplification. Ectopic expression of STK15
in mouse NIH 3T3 cells led to the appearance of abnormal centrosome number (amplification) and transformation in vitro
. Finally, overexpression of STK15
in near diploid human breast epithelial cells revealed similar centrosome abnormality, as well as induction of aneuploidy. These findings suggest that STK15
is a critical kinase-encoding gene, whose overexpression leads to centrosome amplification, chromosomal instability and transformation in mammalian cells.
1,302 citations
"Aurora A kinase (AURKA) in normal a..." refers background in this paper
...In 1998, two independent studies for the first time identified significant upregulation of Aurora A as a common feature of multiple classes of common solid cancers, including colorectal, breast, ovarian, prostate, neuroblastoma, and cervical, in both primary tumor tissue and cell lines [153, 154]....
[...]
...A number of these phenotypes arise from the failure of cytokinesis in cells with overexpressed Aurora A, resulting in initial accumulation of centrosomes [11, 154]....
[...]
TL;DR: It is demonstrated that the Aurora2 gene maps to chromosome 20q13, a region amplified in a variety of human cancers, including a significant number of colorectal malignancies, which implicate aurora2 as a potential oncogene in many colon, breast and other solid tumors, and identify centrosome‐associated proteins as novel targets for cancer therapy.
Abstract: Genetic and biochemical studies in lower eukaryotes have identified several proteins that ensure accurate segregation of chromosomes. These include the Drosophila aurora and yeast Ipl1 kinases that are required for centrosome maturation and chromosome segregation. We have identified two human homologues of these genes, termed aurora1 and aurora2, that encode cell-cycle-regulated serine/threonine kinases. Here we demonstrate that the aurora2 gene maps to chromosome 20q13, a region amplified in a variety of human cancers, including a significant number of colorectal malignancies. We propose that aurora2 may be a target of this amplicon since its DNA is amplified and its RNA overexpressed, in more than 50% of primary colorectal cancers. Furthermore, overexpression of aurora2 transforms rodent fibroblasts. These observations implicate aurora2 as a potential oncogene in many colon, breast and other solid tumors, and identify centrosome-associated proteins as novel targets for cancer therapy.
1,271 citations
"Aurora A kinase (AURKA) in normal a..." refers background in this paper
...In 1998, two independent studies for the first time identified significant upregulation of Aurora A as a common feature of multiple classes of common solid cancers, including colorectal, breast, ovarian, prostate, neuroblastoma, and cervical, in both primary tumor tissue and cell lines [153, 154]....
[...]
TL;DR: The size of the single centrosomal body in these circular figures suggests that loss of function of the serine-threonine protein kinase encoded by aur leads to a failure of the centrosomes to separate and form a bipolar spindle.
830 citations