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https://www.readbyqxmd.com/read/29660984/chemically-induced-degradation-of-anaplastic-lymphoma-kinase-alk
#1
Chelsea E Powell, Yang Gao, Li Tan, Katherine A Donovan, Radosław P Nowak, Amanda Loehr, Magda Bahcall, Eric S Fischer, Pasi A Janne, 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)...
April 16, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29656322/p190rhogap-prevents-mitotic-spindle-fragmentation-and-is-required-to-activate-aurora-a-kinase-at-acentriolar-poles
#2
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
https://www.readbyqxmd.com/read/29656197/design-and-synthesis-of-bpr1k653-derivatives-targeting-the-back-pocket-of-aurora-kinases-for-selective-isoform-inhibition
#3
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...
April 3, 2018: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29606879/targeting-dtl-induces-cell-cycle-arrest-and-senescence-and-suppresses-cell-growth-and-colony-formation-through-tpx2-inhibition-in-human-hepatocellular-carcinoma-cells
#4
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
https://www.readbyqxmd.com/read/29571950/aurora-a-regulates-the-architecture-of-the-golgi-apparatus
#5
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...
March 20, 2018: Experimental Cell Research
https://www.readbyqxmd.com/read/29568394/cardiac-glycoside-bufalin-blocks-cancer-cell-growth-by-inhibition-of-aurora-a-and-aurora-b-activation-via-pi3k-akt-pathway
#6
Chuan-Ming Xie, Xiao-Tong Lin, Di Wu, Ye Tan, Christopher H K Cheng, Jun Zhang
In our previous study, cardiac glycosides including bufalin, a group of sodium pump (Na+/K+-ATPase) inhibitors widely used to treat heart failure for many years, have been demonstrated to induce a delay of mitotic entry and mitotic arrest in many cancer cells. However, the underlying mechanism remains poorly understood. Here, we reported for the first time that cardiac glycoside bufalin induced mitotic entry delay and prometaphase arrest by inhibition of activation of Aurora A/B. Furthermore, cardiac glycoside bufalin prevented Aurora A recruitment to mitotic centrosomes and Aurora B recruitment to unattached kinetochores...
March 2, 2018: Oncotarget
https://www.readbyqxmd.com/read/29563798/co-delivery-of-aurora-a-inhibitor-xy-4-and-bcl-xl-sirna-enhances-antitumor-efficacy-for-melanoma-therapy
#7
Xingmei Duan, Minjie Mu, Junfeng Yan, Lan Bai, Lei Zhong, Yuxuan Zhu, Haixia Pan, Mei Zhang, Jianyou Shi
Background: The newly synthesized Aurora-A kinase inhibitor XY-4 is a potential anti-cancer agent, but its hydrophobicity and limited efficiency restrict further application. Nanotechnology based combined therapy provides an optimized strategy for solving these issues. Methods: In this study, the newly synthesized Aurora-A kinase inhibitor XY-4 and Bcl-xl targeted siRNA were co-delivered by cationic liposomes, creating an injectable co-delivery formulation. The anti-cancer ability and mechanisms of XY-4/Bcl-xl siRNA co-loaded cationic liposomes were studied both in vitro and in vivo...
2018: International Journal of Nanomedicine
https://www.readbyqxmd.com/read/29555820/aurora-a-kinase-activity-is-required-to-maintain-the-spindle-assembly-checkpoint-active-during-pro-metaphase
#8
Thibault Courtheoux, Alghassimou Diallo, Arun Prasath Damodaran, David Reboutier, Erwan Watrin, Claude Prigent
During the prometaphase stage of mitosis, the cell builds a bipolar spindle of microtubules that mechanically segregates sister chromatids for two daughter cells in anaphase. The spindle assembly checkpoint (SAC) is a quality control mechanism that monitors proper attachment of microtubules to chromosome kinetochores during prometaphase. Segregation occurs only when each chromosome is bi-oriented with each kinetochore pair attached to microtubules emanating from opposite spindle poles. Overexpression of the protein kinase Aurora A is a feature of various cancers and is thought to enable tumour cells to bypass the SAC leading to aneuploidy...
March 19, 2018: Journal of Cell Science
https://www.readbyqxmd.com/read/29555478/inhibition-of-tacc3-by-a-small-molecule-inhibitor-in-breast-cancer
#9
Loredana Campo, Eun-Kyoung Breuer
Studies have shown that transforming acidic coiled-coil protein 3 (TACC3), a key component of centrosome-microtubule dynamic networks, is significantly associated with various types of human cancer. We have recently reported that high levels of TACC3 are found in breast cancer, lead to the accumulation of spontaneous DNA damage due to defective DNA damage response signaling, and confer cellular sensitivity to radiation and poly(ADP-ribose) polymerase (PARP) inhibitors. Although our study suggests a potential role of TACC3 as a biomarker in breast cancer detection and prediction of therapy outcome, its role as a therapeutic target in breast cancer is not well studied...
March 19, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29545102/discovery-of-a-highly-potent-orally-bioavailable-imidazo-1-2-a-pyrazine-aurora-inhibitor
#10
Tao Yu, Yonglian Zhang, Angela D Kerekes, Jayaram R Tagat, Ronald J Doll, Yushi Xiao, Sara Esposite, Alan Hruza, David B Belanger, Matthew Voss, Matthew P Rainka, Andrea Basso, Ming Liu, Lianzhu Liang, Ning Sui, Daniel Prelusky, Diane Rindgen, Likang Zhang
Imidazo-[1, 2-a]pyrazine 1 is a potent inhibitor of Aurora A and B kinase in vitro and is effective in in vivo tumor models, but has poor oral bioavailbility and is unsuitable for oral dosing. We describe herein our effort to improve oral exposure in this class, resulting ultimately in the identification of a potent Aurora inhibitor 16, which exhibited good drug exposure levels across species upon oral dosing, and showed excellent in vivo efficacy in a mouse xenograft tumor model when dosed orally.
February 23, 2018: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29544896/the-role-of-aurora-a-in-cancer-stem-cells
#11
REVIEW
Minle Li, Keyu Gao, Laili Chu, Junnian Zheng, Jing Yang
Aurora kinase A (Aurora-A), a member of the Aurora family of serine/threonine kinases, plays a critical role in multiple steps of mitotic progression, including microtubule stability during the G1 phase of the cell cycle, chromosome alignment and segregation, and cytokinesis and is aberrantly expressed in various types of human cancers. In addition to its classic functions, recent studies have indicated that Aurora-A is critical for controlling self-renewal of embryonic stem cells through negative regulation of p53...
March 12, 2018: International Journal of Biochemistry & Cell Biology
https://www.readbyqxmd.com/read/29531224/coa-synthase-regulates-mitotic-fidelity-via-cbp-mediated-acetylation
#12
Chao-Chieh Lin, Mayumi Kitagawa, Xiaohu Tang, Ming-Hsin Hou, Jianli Wu, Dan Chen Qu, Vinayaka Srinivas, Xiaojing Liu, J Will Thompson, Bernard Mathey-Prevot, Tso-Pang Yao, Sang Hyun Lee, Jen-Tsan Chi
The temporal activation of kinases and timely ubiquitin-mediated degradation is central to faithful mitosis. Here we present evidence that acetylation controlled by Coenzyme A synthase (COASY) and acetyltransferase CBP constitutes a novel mechanism that ensures faithful mitosis. We found that COASY knockdown triggers prolonged mitosis and multinucleation. Acetylome analysis reveals that COASY inactivation leads to hyper-acetylation of proteins associated with mitosis, including CBP and an Aurora A kinase activator, TPX2...
March 12, 2018: Nature Communications
https://www.readbyqxmd.com/read/29515234/parp10-suppresses-tumor-metastasis-through-regulation-of-aurora-a-activity
#13
Yahui Zhao, Xiaoding Hu, Li Wei, Dan Song, Juanjuan Wang, Lifang You, Hexige Saiyin, Zhaojie Li, Wenbo Yu, Long Yu, Jin Ding, Jiaxue Wu
ADP-ribosylation, including poly-ADP-ribosylation (PARylation) and mono-ADP-ribosylation (MARylation), is a multifunctional post-translational modification catalyzed by intracellular ADP-ribosyltransferases (ARTDs or PARPs). Although PARylation has been investigated most thoroughly, the function of MARylation is currently largely undefined. Here, we provide evidences that deficiency of PARP10, a mono-ADP-ribosyltransferase, markedly increased the migration and invasion of tumor cells through regulation of epithelial-mesenchymal transition (EMT), and PARP10 inhibited tumor metastasis in vivo, which was dependent on its enzyme activity...
March 8, 2018: Oncogene
https://www.readbyqxmd.com/read/29510984/mitotic-spindle-association-of-tacc3-requires-aurora-a-dependent-stabilization-of-a-cryptic-%C3%AE-helix
#14
Selena G Burgess, Manjeet Mukherjee, Sarah Sabir, Nimesh Joseph, Cristina Gutiérrez-Caballero, Mark W Richards, Nicolas Huguenin-Dezot, Jason W Chin, Eileen J Kennedy, Mark Pfuhl, Stephen J Royle, Fanni Gergely, Richard Bayliss
Aurora-A regulates the recruitment of TACC3 to the mitotic spindle through a phospho-dependent interaction with clathrin heavy chain (CHC). Here, we describe the structural basis of these interactions, mediated by three motifs in a disordered region of TACC3. A hydrophobic docking motif binds to a previously uncharacterized pocket on Aurora-A that is blocked in most kinases. Abrogation of the docking motif causes a delay in late mitosis, consistent with the cellular distribution of Aurora-A complexes. Phosphorylation of Ser558 engages a conformational switch in a second motif from a disordered state, needed to bind the kinase active site, into a helical conformation...
March 6, 2018: EMBO Journal
https://www.readbyqxmd.com/read/29491003/oncoprotein-cip2a-promotes-the-disassembly-of-primary-cilia-and-inhibits-glycolytic-metabolism
#15
Ae Lee Jeong, Hye In Ka, Sora Han, Sunyi Lee, Eun-Woo Lee, Su Jung Soh, Hyun Jeong Joo, Buyanravjkh Sumiyasuren, Ji Young Park, Jong-Seok Lim, Jong Hoon Park, Myung Sok Lee, Young Yang
In most mammalian cells, the primary cilium is a microtubule-enriched protrusion of the plasma membrane and acts as a key coordinator of signaling pathways during development and tissue homeostasis. The primary cilium is generated from the basal body, and cancerous inhibitor of protein phosphatase 2A (CIP2A), the overexpression of which stabilizes c-MYC to support the malignant growth of tumor cells, is localized in the centrosome. Here, we show that CIP2A overexpression induces primary cilia disassembly through the activation of Aurora A kinase, and CIP2A depletion increases ciliated cells and cilia length in retinal pigment epithelium (RPE1) cells...
February 28, 2018: EMBO Reports
https://www.readbyqxmd.com/read/29472535/egf-receptor-kinase-suppresses-ciliogenesis-through-activation-of-usp8-deubiquitinase
#16
Kousuke Kasahara, Hiromasa Aoki, Tohru Kiyono, Shujie Wang, Harumi Kagiwada, Mizuki Yuge, Toshio Tanaka, Yuhei Nishimura, Akira Mizoguchi, Naoki Goshima, Masaki Inagaki
Ciliogenesis is generally inhibited in dividing cells, however, it has been unclear which signaling cascades regulate the phenomenon. Here, we report that epidermal growth factor receptor (EGFR) kinase suppresses ciliogenesis by directly phosphorylating the deubiquitinase USP8 on Tyr-717 and Tyr-810 in RPE1 cells. These phosphorylations elevate the deubiquitinase activity, which then stabilizes the trichoplein-Aurora A pathway, an inhibitory mechanism of ciliogenesis. EGFR knockdown and serum starvation result in ciliogenesis through downregulation of the USP8-trichoplein-Aurora A signal...
February 22, 2018: Nature Communications
https://www.readbyqxmd.com/read/29468452/leptin-regulates-the-pro-inflammatory-response-in-human-epidermal-keratinocytes
#17
Moonyoung Lee, Eunyoung Lee, Sun Hee Jin, Sungjin Ahn, Sae On Kim, Jungmin Kim, Dalwoong Choi, Kyung-Min Lim, Seung-Taek Lee, Minsoo Noh
The role of leptin in cutaneous wound healing process has been suggested in genetically obese mouse studies. However, the molecular and cellular effects of leptin on human epidermal keratinocytes are still unclear. In this study, the whole-genome-scale microarray analysis was performed to elucidate the effect of leptin on epidermal keratinocyte functions. In the leptin-treated normal human keratinocytes (NHKs), we identified the 151 upregulated and 53 downregulated differentially expressed genes (DEGs). The gene ontology (GO) enrichment analysis with the leptin-induced DEGs suggests that leptin regulates NHKs to promote pro-inflammatory responses, extracellular matrix organization, and angiogenesis...
February 21, 2018: Archives of Dermatological Research
https://www.readbyqxmd.com/read/29467234/correction-cip2a-acts-as-a-scaffold-for-cep192-mediated-microtubule-organizing-center-assembly-by-recruiting-plk1-and-aurora-a-during-meiotic-maturation-doi-10-1242-dev-158584
#18
HaiYang Wang, Min Ho Choe, In-Won Lee, Suk Namgoong, Jae-Sung Kim, Nam-Hyung Kim, Jeong Su Oh
No abstract text is available yet for this article.
February 21, 2018: Development
https://www.readbyqxmd.com/read/29465396/a-dynamic-mechanism-for-allosteric-activation-of-aurora-kinase-a-by-activation-loop-phosphorylation
#19
Emily F Ruff, Joseph M Muretta, Andrew R Thompson, Eric W Lake, Soreen Cyphers, Steven K Albanese, Sonya M Hanson, Julie M Behr, David D Thomas, John D Chodera, Nicholas M Levinson
Many eukaryotic protein kinases are activated by phosphorylation on a specific conserved residue in the regulatory activation loop, a post-translational modification thought to stabilize the active DFG-In state of the catalytic domain. Here we use a battery of spectroscopic methods that track different catalytic elements of the kinase domain to show that the ~100-fold activation of the mitotic kinase Aurora A (AurA) by phosphorylation occurs without a population shift from the DFG-Out to the DFG-In state, and that the activation loop of the activated kinase remains highly dynamic...
February 21, 2018: ELife
https://www.readbyqxmd.com/read/29463553/concurrent-inhibition-of-neurosphere-and-monolayer-cells-of-pediatric-glioblastoma-by-aurora-a-inhibitor-mln8237-predicted-survival-extension-in-pdox-models
#20
Xiao-Nan Li, Mari Kogiso, Lin Qi, Frank K Braun, Sarah G Injac, Linna Zhang, Yuchen Du, Huiyuan Zhang, Frank Y Lin, Sibo Zhao, Holly Lindsay, Jack Mf Su, Patricia A Baxter, Adekunle M Adesina, Debra Liao, Mark G Qian, Stacey L Berg, Jodi Muscal
PURPOSE: Pediatric glioblastoma (pGBM) is highly aggressive tumor in need of novel therapies. Our objective was to demonstrate the therapeutic efficacy of MLN8237 (Alisertib), an orally available selective inhibitor of Aurora A kinase (AURKA), and to evaluate which in vitro model system (monolayer or neurosphere) can predict therapeutic efficacy in vivo. EXPERIMENTAL DESIGN: AURKA mRNA expressions were screened with qRT-PCR. In vitro anti-tumor effects were examined in 3 matching pairs of monolayer and neurosphere lines established from patient derived orthotopic xenograft (PDOX) models of the untreated (IC-4687GBM), recurrent (IC-372GBM) and terminal (IC-R0315GBM) tumors; and in vivo therapeutic efficacy through log rank analysis of survival times in 2 models (IC-4687GBM and IC-R0315GBM) following MLN8237 treatment (30 mg/kg/day, p...
February 20, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
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