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Aurora kinase

Benjamin A Farber, Gadi Lalazar, Elana P Simon, William J Hammond, David Requena, Umesh K Bhanot, Michael P La Quaglia, Sanford M Simon
Fibrolamellar hepatocellular carcinoma (FLC) is a rare primary liver cancer found in adolescents and young adults without underlying liver disease. A deletion of ~400 kD has been found in one copy of chromosome 19 in the tumor tissue of all patients tested. This produces a fusion of the genes DNAJB1 and PRKACA which, in turn, produces a chimeric transcript and protein. Transcriptomic analysis of the tumor has shown upregulation of various oncologically relevant pathways, including EGF/ErbB, Aurora Kinase A, pak21 and wnt...
February 13, 2018: Oncotarget
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
Hironori Inaba, Daishi Yamakawa, Yasuko Tomono, Atsushi Enomoto, Shinji Mii, Kousuke Kasahara, Hidemasa Goto, Masaki Inagaki
We previously reported that vimentin, GFAP, and desmin (type III intermediate filament [IF] proteins) are mitotically phosphorylated by CDK1, Aurora-B, and Rho-kinase. This phosphorylation is critical for efficient separation of these IFs and completion of cytokinesis. Keratin 5 (K5) and K14 form a heterodimer, which constitutes IF network in basal layer cells of stratified squamous epithelia. Here, we report that the solubility of K5/K14 increased in mitosis. The in vitro assays revealed that three mitotic kinases phosphorylate K5 more than K14...
March 5, 2018: Biochemical and Biophysical Research Communications
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
Hironori Funabiki, Christopher Jenness, Christian Zierhut
The majority of eukaryotic chromosomal DNA exists in the form of nucleosomes, where ∼147 bp DNA wraps around histone hetero-octamers, composed of histone H3, H4, H2A, and H2B. Despite their obvious importance in DNA compaction and accessibility, studying their specific roles, such as regulation of mitotic progression, in a physiological environment is associated with critical caveats because of their major contributions in transcriptional control. Through establishing a method to deplete endogenous histones H3 and H4 from frog egg extracts and complementing their functions using recombinant nucleosome arrays, we are now able to analyze their roles in mitotic progression without affecting overall transcriptomic profiles...
March 7, 2018: Cold Spring Harbor Symposia on Quantitative Biology
Liwei Li, Yue Song, Qing Liu, Xi Liu, Rui Wang, Chunsheng Kang, Qingyu Zhang
Gastric adenocarcinoma remains a life‑threatening disease, emphasizing the importance of gaining an improved understanding of signaling pathways involved in this disease, which can lead to the development of novel therapeutic methods targeting common molecular pathways shared across different types of gastric adenocarcinoma. The present study revealed phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and aurora kinase A (AURKA) gene alterations, which were involved in changes in the phenotypes of gastric cancer cells, including increased proliferation by cell counting kit‑8 assay and invasion capacity by Transwell invasion assay, and predicted survival rates by KM Plotter database in gastric cancer...
March 7, 2018: International Journal of Molecular Medicine
Jing Cao, Xiao-Ming Liu, Li-Lin Huang, Li Wang, Xiao-Fei Jiao, Li-Jun Huo
In the mammalian ovary, >99% follicles fail to ovulate due to apoptosis in granulosa cells. Aurora B, a core subunit enzyme of the chromosomal passenger complex, exerts a crucial role in microtubule‑kinetochore attachment, and has been reported to be modified by small ubiquitin‑related modifier (SUMO) proteins. However, the details of how Aurora B and its SUMOylation impact on follicular development have yet to be fully elucidated. The aim of the present study was to explore the roles, and possible molecular mechanism, of Aurora B and its SUMOylation in the granulosa cells of the mouse follicle...
March 7, 2018: International Journal of Molecular Medicine
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
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
Ksenia Krupina, Charlotte Kleiss, Sushil Awal, Irene Rodriguez-Hernandez, Victoria Sanz-Moreno, Izabela Sumara
Defects in mitosis can lead to aneuploidy, which is a common feature of human cancers. Spindle Assembly Checkpoint (SAC) controls fidelity of chromosome segregation in mitosis to prevent aneuploidy. The ubiquitin receptor protein Ubiquitin Associated and SH3 Domain Containing B (UBASH3B) was recently found to control SAC silencing and faithful chromosome segregation by relocalizing Aurora B kinase to the mitotic microtubules. Accordingly, loss and gain of function of UBASH3B have strong effects on mitotic progression...
2018: Molecular & Cellular Oncology
Jin Woo Park, Hana Cho, Hyein Oh, Ji-Young Kim, Sang-Beom Seo
Aberrations in histone modifications are being studied in mixed-lineage leukemia (MLL)-AF9-driven acute myeloid leukemia (AML). In this study, we focused on the regulation of the differentiation of the MLL-AF9 type AML cell line THP-1. We observed that, upon phorbol 12-myristate 13-acetate (PMA) treatment, THP-1 cells differentiated into monocytes by down-regulating Aurora kinase A (AURKA), resulting in a reduction in H3S10 phosphorylation. We revealed that the AURKA inhibitor alisertib accelerates the expression of the H3K27 demethylase KDM6B, thereby dissociating AURKA and YY1 from the KDM6B promoter region...
February 23, 2018: Molecules and Cells
Russell Payne, Oliver D Mrowczynski, Becky Slagle-Webb, Alexandre Bourcier, Christine Mau, Dawit Aregawi, Achuthamangalam B Madhankumar, Sang Y Lee, Kimberly Harbaugh, James Connor, Elias B Rizk
OBJECTIVE Malignant peripheral nerve sheath tumors (MPNSTs) are soft-tissue sarcomas arising from peripheral nerves. MPNSTs have increased expression of the oncogene aurora kinase A, leading to enhanced cellular proliferation. This makes them extremely aggressive with high potential for metastasis and a devastating prognosis; 5-year survival estimates range from a dismal 15% to 60%. MPNSTs are currently treated with resection (sometimes requiring limb amputation) in combination with chemoradiation, both of which demonstrate limited effectiveness...
February 23, 2018: Journal of Neurosurgery
Yukie Kashima, Ayako Suzuki, Ying Liu, Masahito Hosokawa, Hiroko Matsunaga, Masataka Shirai, Kohji Arikawa, Sumio Sugano, Takashi Kohno, Haruko Takeyama, Katsuya Tsuchihara, Yutaka Suzuki
Single-cell RNA-seq is a powerful tool for revealing heterogeneity in cancer cells. However, each of the current single-cell RNA-seq platforms has inherent advantages and disadvantages. Here, we show that combining the different single-cell RNA-seq platforms can be an effective approach to obtaining complete information about expression differences and a sufficient cellular population to understand transcriptional heterogeneity in cancers. We demonstrate that it is possible to estimate missing expression information...
February 22, 2018: Scientific Reports
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
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
Serene S L Gwee, Rowan A W Radford, Sharron Chow, Monisha D Syal, Marco Morsch, Isabel Formella, Albert Lee, Emily K Don, Andrew P Badrock, Nicholas J Cole, Adrian K West, Steve N S Cheung, Roger S Chung
Aurora kinase B (AurkB) is a serine/threonine protein kinase with a well-characterised role in orchestrating cell division and cytokinesis, and is prominently expressed in healthy proliferating and cancerous cells. However, the role of AurkB in differentiated and non-dividing cells has not been extensively explored. Previously, we have described a significant upregulation of AurkB expression in cultured cortical neurons following an experimental axonal transection. This is somewhat surprising, as AurkB expression is generally associated only with dividing cells Frangini et al...
February 21, 2018: Cellular and Molecular Life Sciences: CMLS
Jan G Ruppert, Kumiko Samejima, Melpomeni Platani, Oscar Molina, Hiroshi Kimura, A Arockia Jeyaprakash, Shinya Ohta, William C Earnshaw
The chromosomal passenger complex (CPC) is directed to centromeres during mitosis via binding to H3T3ph and Sgo1. Whether and how heterochromatin protein 1α (HP1α) influences CPC localisation and function during mitotic entry is less clear. Here, we alter HP1α dynamics by fusing it to a CENP-B DNA-binding domain. Tethered HP1 strongly recruits the CPC, destabilising kinetochore-microtubule interactions and activating the spindle assembly checkpoint. During mitotic exit, the tethered HP1 traps active CPC at centromeres...
February 21, 2018: EMBO Journal
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
Ye Hong, Remi Sonneville, Bin Wang, Viktor Scheidt, Bettina Meier, Alexander Woglar, Sarah Demetriou, Karim Labib, Verena Jantsch, Anton Gartner
Faithful chromosome segregation and genome maintenance requires the removal of all DNA bridges that physically link chromosomes before cells divide. Using C. elegans embryos we show that the LEM-3/Ankle1 nuclease defines a previously undescribed genome integrity mechanism by processing DNA bridges right before cells divide. LEM-3 acts at the midbody, the structure where abscission occurs at the end of cytokinesis. LEM-3 localization depends on factors needed for midbody assembly, and LEM-3 accumulation is increased and prolonged when chromatin bridges are trapped at the cleavage plane...
February 20, 2018: Nature Communications
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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