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Yu-Chuan Huang, Chung-Ta Lee, Jenq-Chang Lee, Yao-Wen Liu, Ying-Jen Chen, Joseph T Tseng, Jui-Wen Kang, Bor-Shyang Sheu, Bo-Wen Lin, Liang-Yi Hung
MicorRNA-137 is silenced in human colorectal cancer tissues and colon polyps. Our study showed that the decreased expression of miR-137 is significantly different in various types of polyp which maintain different potentials to lead to CRC development. The expression of miR-137 gradually decreases during the process of colorectal carcinogenesis. Receiver operating characteristic curve (ROC) analysis indicates that the loss of miR-137 expression in colon polyps can serve as a biomarker to predict the predisposition of colorectal carcinogenesis...
October 18, 2016: Oncotarget
Jacek Z Kubiak, Claude Prigent
The aim of this short review is to describe the contribution of Xenopus laevis egg extracts to the discovery and understanding of the regulation and function of the serine/threonine kinase Aurora-A. The power of these extracts to recapitulate cell cycle events makes them a precious tool to decipher complex biological processes at the molecular level, including the mechanisms that affect Aurora-A (post-translational modifications) and mechanisms in which Aurora-A plays a crucial role (bipolar spindle assembly)...
2016: International Journal of Developmental Biology
W Bruinsma, M Aprelia, I García-Santisteban, J Kool, Y J Xu, R H Medema
When cells in G2 phase are challenged with DNA damage, several key mitotic regulators such as Cdk1/Cyclin B, Aurora A and Plk1 are inhibited to prevent entry into mitosis. Here we have studied how inhibition of Plk1 is established after DNA damage. Using a Förster resonance energy transfer (FRET)-based biosensor for Plk1 activity, we show that inhibition of Plk1 after DNA damage occurs with relatively slow kinetics and is entirely dependent on loss of Plk1-T210 phosphorylation. As T210 is phosphorylated by the kinase Aurora A in conjunction with its co-factor Bora, we investigated how they are affected by DNA damage...
October 10, 2016: Oncogene
Yoo Hong Min, Wootae Kim, Ja-Eun Kim
Mitotic progression is crucial for the maintenance of chromosomal stability. A proper progression is ensured by the activities of multiple kinases. One of these enzymes, the serine/threonine kinase Aurora A, is required for proper mitosis through the regulation of centrosome and spindle assembly. In this study, we functionally characterized a newly developed Aurora kinase A inhibitor, TC-A2317. In human lung cancer cells, TC-A2317 slowed proliferation by causing aberrant formation of centrosome and microtubule spindles and prolonging the duration of mitosis...
October 4, 2016: Oncotarget
Hidemasa Goto, Hironori Inaba, Masaki Inagaki
The primary cilium is a non-motile and microtubule-enriched protrusion ensheathed by plasma membrane. Primary cilia function as mechano/chemosensors and signaling hubs and their disorders predispose to a wide spectrum of human diseases. Most types of cells assemble their primary cilia in response to cellular quiescence, whereas they start to retract the primary cilia upon cell-cycle reentry. The retardation of ciliary resorption process has been shown to delay cell-cycle progression to the S or M phase after cell-cycle reentry...
September 26, 2016: Cellular and Molecular Life Sciences: CMLS
Anna A Ye, Julia Torabi, Thomas J Maresca
During cytokinesis, aurora B kinase (ABK) relocalizes from centromeres to the spindle midzone, where it is thought to provide a spatial cue for cytokinesis. While global ABK inhibition in Drosophila S2 cells results in macro- and multi-nucleated large cells, mislocalization of midzone ABK (mABK) by depletion of Subito (Drosophila MKLP2) does not cause notable cytokinesis defects. Subito depletion was, therefore, used to investigate the contribution of other molecules and redundant pathways to cytokinesis in the absence of mABK...
August 2016: Biological Bulletin
Nélida Inés Noguera, Maria Liliana Piredda, Riccardo Taulli, Gianfranco Catalano, Giulia Angelini, Girish Gaur, Clara Nervi, Maria Teresa Voso, Andrea Lunardi, Pier Paolo Pandolfi, Francesco Lo-Coco
Acute promyelocitic leukemia (APL) is characterized by the pathognomonic presence in leukemic blasts of the hybrid protein PML/RARA, that acts as a transcriptional repressor impairing the expression of genes that are critical to myeloid differentiation. Here, we show that primary blasts from APL patients express lower levels of the oncosuppressor protein PTEN, as compared to blast cells from other AML subtypes or normal bone marrow, and demonstrate that PML-RARA directly inhibits PTEN expression. We show that All-Trans Retinoic Acid (ATRA) triggers in APL cells an active chromatin status at the core regulatory region of the PTEN promoter, that allows the binding of the myeloid-regulating transcription factor PU...
September 10, 2016: Oncotarget
Giulia Bertolin, Florian Sizaire, Gaëtan Herbomel, David Reboutier, Claude Prigent, Marc Tramier
Overexpression of AURKA is a major hallmark of epithelial cancers. It encodes the multifunctional serine/threonine kinase aurora A, which is activated at metaphase and is required for cell cycle progression; assessing its activation in living cells is mandatory for next-generation drug design. We describe here a Förster's resonance energy transfer (FRET) biosensor detecting the conformational changes of aurora kinase A induced by its autophosphorylation on Thr288. The biosensor functionally replaces the endogenous kinase in cells and allows the activation of the kinase to be followed throughout the cell cycle...
2016: Nature Communications
Warapen Treekitkarnmongkol, Hiroshi Katayama, Kazuharu Kai, Kaori Sasai, Jennifer Carter Jones, Jing Wang, Li Shen, Aysegul A Sahin, Mihai Gagea, Naoto T Ueno, Chad J Creighton, Subrata Sen
Recent data from The Cancer Genome Atlas analysis have revealed that Aurora kinase A (AURKA) amplification and overexpression characterize a distinct subset of human tumors across multiple cancer types. Although elevated expression of AURKA has been shown to induce oncogenic phenotypes in cells in vitro, findings from transgenic mouse models of Aurora-A overexpression in mammary glands have been distinct depending on the models generated. In the present study, we report that prolonged overexpression of AURKA transgene in mammary epithelium driven by ovine β-lactoglobulin promoter, activated through multiple pregnancy and lactation cycles, results in the development of mammary adenocarcinomas with alterations in cancer-relevant genes and epithelial-to-mesenchymal transition...
September 13, 2016: Carcinogenesis
S-S Chang, H Yamaguchi, W Xia, S-O Lim, Y Khotskaya, Y Wu, W-C Chang, Q Liu, M-C Hung
The Yes-associated protein (YAP) is an effector that transduces the output of the Hippo pathway to transcriptional modulation. Considering the role of YAP in cancers, this protein has emerged as a key node in malignancy development. In this study, we determined that Aurora A kinase acts as a positive regulator for YAP-mediated transcriptional machinery. Specifically, YAP associates with Aurora A predominantly in the nucleus. Activation of Aurora A can impinge on YAP activity through direct phosphorylation. Moreover, aberrant expression of YAP and Aurora A signaling is highly correlated with triple-negative breast cancer (TNBC)...
September 5, 2016: Oncogene
Joost C M Uitdehaag, Jeroen A D M de Roos, Martine B W Prinsen, Nicole Willemsen-Seegers, Judith R F de Vetter, Jelle Dylus, Antoon M van Doornmalen, Jeffrey Kooijman, Masaaki Sawa, Suzanne J C van Gerwen, Jos de Man, Rogier C Buijsman, Guido J R Zaman
Cancer cell line panels are important tools to characterize the in vitro activity of new investigational drugs. Here we present the inhibition profiles of 122 anti-cancer agents in proliferation assays with 44 or 66 genetically characterized cancer cell lines from diverse tumor tissues (Oncolines™). The library includes 29 cytotoxics, 68 kinase inhibitors and 11 epigenetic modulators. For 38 compounds this is the first comparative profiling in a cell line panel. By strictly maintaining optimized assay protocols, biological variation was kept to a minimum...
September 1, 2016: Molecular Cancer Therapeutics
Chun-Feng Chang, Wen-Hsing Lin, Yi-Yu Ke, Yih-Shyan Lin, Wen-Chieh Wang, Chun-Hwa Chen, Po-Chu Kuo, John T A Hsu, Biing-Jiun Uang, Hsing-Pang Hsieh
Aurora kinases have emerged as important anticancer targets so that there are several inhibitors have advanced into clinical study. Herein, we identified novel indazole derivatives as potent Aurora kinases inhibitors by utilizing in silico fragment-based approach and knowledge-based drug design. After intensive hit-to-lead optimization, compounds 17 (dual Aurora A and B), 21 (Aurora B selective) and 30 (Aurora A selective) possessed indazole privileged scaffold with different substituents, which provide sub-type kinase selectivity...
August 16, 2016: European Journal of Medicinal Chemistry
Estelle Willems, Arnaud Lombard, Matthias Dedobbeleer, Nicolas Goffart, Bernard Rogister
The main obstacle for the cure of glioblastoma (GBM) is systematic tumor recurrence after treatment. More than 90 % of GBM tumors are indeed recurrent within 5 years after diagnosis and treatment. We urgently need new therapies to specifically address these deadly relapses. A major advance in the understanding of GBM recurrence is the identification of GBM-Initiating Cells (GIC), characterized by their abilities for self-renewal, multilineage differentiation, and proliferation. It appears that these features of GIC could be modulated by the mitotic kinase Aurora A (AurA)...
August 29, 2016: Targeted Oncology
Ning Zhong, Shunbin Shi, Hongzhen Wang, Guangzhou Wu, Yunliang Wang, Qiang Ma, Hongwei Wang, Yuanhua Liu, Jinzhi Wang
Aurora kinase A (AURKA) is an oncogenic serine/threonine kinase, it plays important roles in tumorigenesis and chemoresistance. In this study, we investigated the expression of AURKA in lung adenocarcinoma tissues, the role of small interference RNA targeting AURKA on growth, cell cycle, and apoptosis of lung adenocarcinoma cell lines in vitro. The AURKA is highly expressed in lung adenocarcinoma tissues and human lung adenocarcinoma cell lines. Lentivirus-mediated short hairpin RNA (shRNA) was used to knock down AURKA expression in human lung adenocarcinoma cell lines H1299 and A549...
September 2016: International Journal of Oncology
Francesco Meghini, Torcato Martins, Xavier Tait, Kazuyuki Fujimitsu, Hiroyuki Yamano, David M Glover, Yuu Kimata
A multi-subunit ubiquitin ligase, the anaphase-promoting complex/cyclosome (APC/C), regulates critical cellular processes including the cell cycle. To accomplish its diverse functions, APC/C activity must be precisely regulated in time and space. The interphase APC/C activator Fizzy-related (Fzr or Cdh1) is localized at centrosomes in animal cells. However, neither the mechanism of its localization nor its importance is clear. Here we identify the centrosome component Spd2 as a major partner of Fzr in Drosophila...
2016: Nature Communications
Jarom Yan-Ming Chung, Judith Arunodhaya Steen, Thomas Lewis Schwarz
While interphase mitochondria associate with microtubules, mitotic mitochondria dissociate from spindle microtubules and localize in the cell periphery. Here, we show that this redistribution is not mediated by mitochondrial active transport or tethering to the cytoskeleton. Instead, kinesin and dynein, which link mitochondria to microtubules, are shed from the mitochondrial surface. Shedding is driven by phosphorylation of mitochondrial and cytoplasmic targets by CDK1 and Aurora A. Forced recruitment of motor proteins to mitotic mitochondria to override this shedding prevents their proper symmetrical distribution and disrupts the balanced inheritance of mitochondria to daughter cells...
August 23, 2016: Cell Reports
Markus Brockmann, Evon Poon, Teeara Berry, Anne Carstensen, Hedwig E Deubzer, Lukas Rycak, Yann Jamin, Khin Thway, Simon P Robinson, Frederik Roels, Olaf Witt, Matthias Fischer, Louis Chesler, Martin Eilers
No abstract text is available yet for this article.
August 8, 2016: Cancer Cell
Vasilis P Androutsopoulos, Irene Fragiadaki, Demetrios A Spandidos, Androniki Tosca
Resveratrol is a natural dietary product that has demonstrated multifaceted anticancer activity. Several analogues of resveratrol have been synthesized in an effort to enhance the pharmacological potency and improve the pharmacokinetic properties of the compound. 3,4,5,4'‑trans‑tetramethoxystilbene (3,4,5,4'‑TMS) is a methoxylated analogue of resveratrol that has demonstrated anti-proliferative activity in vitro (in cancer cell lines) and in vivo (in xenograft models). In the present study, the anticancer effects of 3,4,5,4'‑TMS in A375 human melanoma cells were examined...
October 2016: International Journal of Oncology
Patrizia Sini, Ulrich Gürtler, Stephan K Zahn, Christoph Baumann, Dorothea Rudolph, Rosa Baumgartinger, Eva Strauss, Christian Haslinger, Ulrike Tontsch-Grunt, Irene C Waizenegger, Flavio Solca, Gerd Bader, Andreas Zoephel, Matthias Treu, Ulrich Reiser, Pilar Garin-Chesa, Guido Boehmelt, Norbert Kraut, Jens Quant, Günther R Adolf
Although the MAPK pathway is frequently deregulated in cancer, inhibitors targeting RAF or MEK have so far shown clinical activity only in BRAF- and NRAS-mutant melanoma. Improvements in efficacy may be possible by combining inhibition of mitogenic signal transduction with inhibition of cell-cycle progression. We have studied the preclinical pharmacology of BI 847325, an ATP-competitive dual inhibitor of MEK and Aurora kinases. Potent inhibition of MEK1/2 and Aurora A/B kinases by BI 847325 was demonstrated in enzymatic and cellular assays...
October 2016: Molecular Cancer Therapeutics
Barbara A Helfrich, Jihye Kim, Dexiang Gao, Daniel C Chan, Zhiyong Zhang, Aik-Choon Tan, Paul A Bunn
Small-cell lung cancer (SCLC) cells have rapid proliferation, universal Rb inactivation, and high rates of MYC family amplification, making aurora kinase inhibition a natural target. Preclinical studies have demonstrated activity for Aurora A and pan-Aurora inhibitors with some relationship to MYC family expression. A clinical trial showed activity for an Aurora kinase A inhibitor, but no biomarkers were evaluated. We screened a panel of 23 SCLC lines with and without MYC family gene amplification or high MYC family gene expression for growth inhibition by the highly potent, selective aurora kinase B inhibitor barasertib...
October 2016: Molecular Cancer Therapeutics
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