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Warintra Pitsawong, Vanessa Buosi, Renee Otten, Roman V Agafonov, Adelajda Zorba, Nadja Kern, Steffen Kutter, Gunther Kern, Ricardo Ap Pádua, Xavier Meniche, Dorothee Kern
Protein kinases are major drug targets, but the development of highly-selective inhibitors has been challenging due to the similarity of their active sites. The observation of distinct structural states of the fully-conserved Asp-Phe-Gly (DFG) loop has put the concept of conformational selection for the DFG-state at the center of kinase drug discovery. Recently, it was shown that Gleevec selectivity for the Tyr-kinases Abl was instead rooted in conformational changes after drug binding. Here, we investigate whether protein dynamics after binding is a more general paradigm for drug selectivity by characterizing the binding of several approved drugs to the Ser/Thr-kinase Aurora A...
June 14, 2018: ELife
Rhys Grant, Ahmed Abdelbaki, Alessia Bertoldi, Maria P Gavilan, Jörg Mansfeld, David M Glover, Catherine Lindon
Aurora A kinase (AURKA) is a major regulator of mitosis and an important driver of cancer progression. The roles of AURKA outside of mitosis, and how these might contribute to cancer progression, are not well understood. Here, we show that a fraction of cytoplasmic AURKA is associated with mitochondria, co-fractionating in cell extracts and interacting with mitochondrial proteins by reciprocal co-immunoprecipitation. We have also found that the dynamics of the mitochondrial network are sensitive to AURKA inhibition, depletion or overexpression...
June 2018: Open Biology
Yu-Chu Wang, Kung-Chao Chang, Bo-Wen Lin, Jenq-Chang Lee, Chien-Hsien Lai, Li-Jyuan Lin, Yun Yen, Chang-Shen Lin, Shiang-Jie Yang, Peng-Chan Lin, Chung-Ta Lee, Liang-Yi Hung
Heterogeneous nuclear ribonucleoprotein (hnRNP) Q1, an RNA-binding protein, has been implicated in many post-transcriptional processes, including RNA metabolism and mRNA splicing and translation. However, the role of hnRNP Q1 in tumorigenesis remains unclear. We previously performed RNA immunoprecipitation (RIP)-seq analysis to identify hnRNP Q1-interacting mRNAs and found that hnRNP Q1 targets a group of genes that are involved in mitotic regulation, including Aurora-A. Here, we demonstrate that altering the hnRNP Q1 level influences the expression of the Aurora-A protein, but not its mRNA...
June 6, 2018: Experimental & Molecular Medicine
Suzanne Vigneron, Lena Sundermann, Jean-Claude Labbé, Lionel Pintard, Ovidiu Radulescu, Anna Castro, Thierry Lorca
Mitosis is induced by the activation of the cyclin B/cdk1 feedback loop that creates a bistable state. The triggering factor promoting active cyclin B/cdk1 switch has been assigned to cyclin B/cdk1 accumulation during G2. However, this complex is rapidly inactivated by Wee1/Myt1-dependent phosphorylation of cdk1 making unlikely a triggering role of this kinase in mitotic commitment. Here we show that cyclin A/cdk1 kinase is the factor triggering mitosis. Cyclin A/cdk1 phosphorylates Bora to promote Aurora A-dependent Plk1 phosphorylation and activation and mitotic entry...
June 4, 2018: Developmental Cell
Ge Zheng, Hongtao Yu
Mitotic entry is an irreversible cell-cycle transition that requires the robust, rapid activation of cyclin-dependent kinase 1 (Cdk1). In this issue of Developmental Cell, Vigneron et al. (2018) identify cyclin A-Cdk1 as the factor triggering mitotic entry through the phosphorylation of Bora, an activator of the kinase Aurora A.
June 4, 2018: Developmental Cell
Yusuke Oku, Naoyuki Nishiya, Shuhei Sugiyama, Haruka Sato, Yoshimasa Uehara
BACKGROUND: Transcriptional co-activators YES-associated protein (YAP) and transcriptional coactivator with PDZ-motif (TAZ) stimulate the expression of cell cycle-related genes to permit for tumour cell growth. MLN8237 is a potent aurora-A kinase inhibitor; however, patients responding to MLN8237 are limited. Therefore, rational combination therapy could enhance their response. MATERIALS AND METHODS: YAP and TAZ were depleted using siRNA and then treated with MLN8237 in YAP/TAZ-dependent OVCAR-8 and MDA-MB-231 cell lines...
June 2018: Anticancer Research
Marquita L Johnson, Rong Wang, Ann O Sperry
Male germ cells are transformed from undifferentiated stem cells into spermatozoa through a series of highly regulated steps together termed spermatogenesis. Spermatogonial stem cells undergo mitosis and differentiation followed by two rounds of meiotic division and then proceed through a series of dramatic cell shape changes to form highly differentiated spermatozoa. Using indirect immunofluorescence, we investigated a role for the mitotic kinase, Aurora A (AURKA) in these events through localization of this protein in mouse testis and spermatozoa...
May 26, 2018: Biochemical and Biophysical Research Communications
Nenggang Zhang, Debananda Pati
Sepin-1, a potent non-competitive inhibitor of separase, inhibits cancer cell growth, but the mechanisms of Sepin-1-mediated growth inhibition are not fully understood. Here we report that Sepin-1 hinders growth of breast cancer cells, cell migration, and wound healing. Inhibition of cell growth induced by Sepin-1 in vitro doesn't appear to be through apoptosis but rather due to growth inhibition. Following Sepin-1 treatment caspases 3 and 7 are not activated and Poly (ADP-ribose) polymerase (Parp) is not cleaved...
2018: Journal of Cancer Science & Therapy
Michael J Bond, Marina Bleiler, Lauren E Harrison, Eric W Scocchera, Masako Nakanishi, Narendran G-Dayanandan, Santosh Keshipeddy, Daniel W Rosenberg, Dennis L Wright, Charles Giardina
AK3 compounds are mitotic-arrest agents that induce high levels of γH2AX during mitosis and apoptosis following release from arrest. We synthesized a potent AK3 derivative, AK306, that induced arrest and apoptosis of the HCT116 colon cancer cell line with an EC50 of ~50 nM. AK306 was active on a broad spectrum of cancer cell lines with total growth inhibition values ranging from ~25 nM to 25 µM. Using biotin and BODIPY-linked derivatives of AK306, binding to clathrin heavy chain (CLTC/CHC) was observed, a protein with roles in endocytosis and mitosis...
May 16, 2018: Molecular Cancer Research: MCR
Arminja N Kettenbach, Kate A Schlosser, Scott P Lyons, Isha Nasa, Jiang Gui, Mark E Adamo, Scott A Gerber
Polo-like kinase 1 (Plk1) is an essential protein kinase that promotes faithful mitotic progression in eukaryotes. The subcellular localization and substrate interactions of Plk1 are tightly controlled and require its binding to phosphorylated residues. To identify phosphorylation-dependent interactions within the Plk1 network in human mitotic cells, we performed quantitative proteomics on HeLa cells cultured with kinase inhibitors or expressing a Plk1 mutant that was deficient in phosphorylation-dependent substrate binding...
May 15, 2018: Science Signaling
Grégory Eot-Houllier, Laura Magnaghi-Jaulin, Géraldine Fulcrand, François-Xavier Moyroud, Solange Monier, Christian Jaulin
Sustained spindle tension applied to sister centromeres during mitosis eventually leads to uncoordinated loss of sister chromatid cohesion, a phenomenon known as "cohesion fatigue." We report that Aurora A-dependent phosphorylation of serine 7 of the centromere histone variant CENP-A (p-CENP-AS7) protects bioriented chromosomes against cohesion fatigue. Expression of a non-phosphorylatable version of CENP-A (CENP-AS7A) weakens sister chromatid cohesion only when sister centromeres are under tension, providing the first evidence of a regulated mechanism involved in protection against passive cohesion loss...
May 14, 2018: Nature Communications
Lucie Vaufrey, Christine Balducci, René Lafont, Claude Prigent, Stéphanie Le Bras
In metazoans, organisms arising from a fertilized egg, the embryo will develop through multiple series of cell divisions, both symmetric and asymmetric, leading to differentiation. Aurora A is a serine threonine kinase highly involved in such divisions. While intensively studied at the cell biology level, its function in the development of a whole organism has been neglected. Here we investigated the pleiotropic effect of Aurora A loss-of-function in Drosophila larval early development. We report that Aurora A is required for proper larval development timing control through direct and indirect means...
May 9, 2018: Developmental Biology
Nadia Al-Hazmi, Turki Alhazzazi, Gareth Williams, Kai Stoeber, Raghad Al-Dabbagh
Oral squamous cell carcinoma (OSCC) is still an unabated global killer with little advancement in its survival rate. DNA replication licensing proteins and Aurora kinase A are biomarkers that play important roles in genomic stability. The expression profile of minichromosomal maintenance protein 2 (MCM2), Ki67, geminin, and Aurora-A were linked to clinicopathological and outcome parameters, survival, and DNA content in 125 cases of OSCC. Oral fibroepithelial polyps (OFEP) were controls. The OSCC tumour cells were in a rapidly proliferating state, as assessed by the increased expression profile of MCM2, Ki67, geminin, and Aurora-A and of the geminin/Ki67 ratio, and the decrease of the MCM2/Ki67 ratio, in OSCC compared with OFEP (P < 0...
June 2018: European Journal of Oral Sciences
Xi Yang, Xinbo Gao, Bin Song, Nannan Wang, Dong Yang
The circular fisheye lens exhibits an approximately 180° angular field-of-view (FOV), which is much larger than that of an ordinary lens. Thus, images captured with a circular fisheye lens are distributed non-uniformly with spherical deformation. Along with the fast development of deep neural networks for normal images, how to apply it to achieve intelligent image processing for a circular fisheye lens is a new task of significant importance. In this paper, we take the aurora images captured with all-sky-imagers (ASI) as a typical example...
April 2, 2018: Optics Express
Jennifer G DeLuca
One of the most important regulatory aspects of chromosome segregation is the ability of kinetochores to precisely control their attachment strength to spindle microtubules. Central to this regulation is Aurora B, a mitotic kinase that phosphorylates kinetochore substrates to promote microtubule turnover. A critical target of Aurora B is the kinetochore protein Ndc80/Hec1, which is a component of the NDC80 complex, the primary force-transducing link between kinetochores and microtubules. Although Aurora B is regarded as the "master regulator" of kinetochore-microtubule attachment, it is becoming clear that this kinase is not solely responsible for phosphorylating Hec1 and other kinetochore substrates to facilitate microtubule turnover...
April 26, 2018: Cold Spring Harbor Symposia on Quantitative Biology
Chelsea E Powell, Yang Gao, Li Tan, Katherine A Donovan, Radosław P Nowak, Amanda Loehr, Magda Bahcall, Eric S Fischer, Pasi A Jänne, Rani E George, Nathanael S Gray
We present the development of the first small molecule degraders that can induce anaplastic lymphoma kinase (ALK) degradation, including in non-small-cell lung cancer (NSCLC), anaplastic large-cell lymphoma (ALCL), and neuroblastoma (NB) cell lines. These degraders were developed through conjugation of known pyrimidine-based ALK inhibitors, TAE684 or LDK378, and the cereblon ligand pomalidomide. We demonstrate that in some cell types degrader potency is compromised by expression of drug transporter ABCB1. In addition, proteomic profiling demonstrated that these compounds also promote the degradation of additional kinases including PTK2 (FAK), Aurora A, FER, and RPS6KA1 (RSK1)...
May 10, 2018: Journal of Medicinal Chemistry
Arkadi Manukyan, Lilit Sargsyan, Sarah J Parsons, P Todd Stukenberg
Assembly of the mitotic spindle is essential for proper chromosome segregation during mitosis. Maintenance of spindle poles requires precise regulation of kinesin- and dynein-generated forces, and improper regulation of these forces disrupts pole integrity leading to pole fragmentation. The formation and function of the mitotic spindle are regulated by many proteins, including Aurora A kinase and the motor proteins Kif2a and Eg5. Here, we characterize a surprising role for the RhoA GTPase-activating protein, p190RhoGAP, in regulating the mitotic spindle...
April 14, 2018: Chromosoma
Yi-Yu Ke, Chun-Ping Chang, Wen-Hsing Lin, Chia-Hua Tsai, I-Chen Chiu, Wan-Ping Wang, Pei-Chen Wang, Pei-Yi Chen, Wen-Hsin Lin, Chun-Feng Chang, Po-Chu Kuo, Jen-Shin Song, Chuan Shih, Hsing-Pang Hsieh, Ya-Hui Chi
Twenty five novel chemical analogs of the previously reported Aurora kinase inhibitor BPR1K653 (1-(4-(2-((5-chloro-6-phenylfuro[2,3-d]pyrimidin-4-yl)amino)ethyl)phenyl)-3-(2-((dimethylamino)methyl)phenyl)urea) have been designed, synthesized, and evaluated by Aurora-A and Aurora-B enzymatic kinase activity assays. Similar to BPR1K653, analogs 3b-3h bear alkyl or tertiary amino group at the ortho position of the phenylurea, and showed equal or better inhibition activity for Aurora-B over Aurora-A. Conversely, preferential Aurora-A inhibition activity was observed when the same functional group was moved to the meta position of the phenylurea...
May 10, 2018: European Journal of Medicinal Chemistry
Yu-Chia Chen, I-Shu Chen, Guan-Jin Huang, Chi-Hsiang Kang, Kuo-Chiang Wang, Min-Jen Tsao, Hung-Wei Pan
Background: Hepatocellular carcinoma (HCC) has an increasing incidence and high mortality. Surgical operation is not a comprehensive strategy for liver cancer. Moreover, tolerating systemic chemotherapy is difficult for patients with HCC because hepatic function is often impaired due to underlying cirrhosis. Therefore, a comprehensive strategy for cancer treatment should be developed. DTL (Cdc10-dependent transcript 2) is a critical regulator of cell cycle progression and genomic stability...
2018: OncoTargets and Therapy
Masashi Kimura, Shuta Takagi, Shigeru Nakashima
The Golgi apparatus plays roles in cell polarity, directional cell migration, and bipolar spindle assembly, as well as the secretary pathway. In addition, recent studies have suggested the Golgi-dependent control of mitotic entry. We studied the role of the centrosomal kinase Aurora A in maintaining the Golgi apparatus. Knockdown of Aurora A resulted in Golgi dispersal during interphase. Golgi dispersal was also induced by a selective Aurora A inhibitor, MLN8237. Conversely, overexpression of Aurora A led to tightly packed Golgi apparatus during interphase...
June 1, 2018: Experimental Cell Research
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