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https://www.readbyqxmd.com/read/28648284/common-molecular-subtypes-among-asian-hepatocellular-carcinoma-and-cholangiocarcinoma
#1
Jittiporn Chaisaingmongkol, Anuradha Budhu, Hien Dang, Siritida Rabibhadana, Benjarath Pupacdi, So Mee Kwon, Marshonna Forgues, Yotsawat Pomyen, Vajarabhongsa Bhudhisawasdi, Nirush Lertprasertsuke, Anon Chotirosniramit, Chawalit Pairojkul, Chirayu U Auewarakul, Thaniya Sricharunrat, Kannika Phornphutkul, Suleeporn Sangrajrang, Maggie Cam, Ping He, Stephen M Hewitt, Kris Ylaya, Xiaolin Wu, Jesper B Andersen, Snorri S Thorgeirsson, Joshua J Waterfall, Yuelin J Zhu, Jennifer Walling, Holly S Stevenson, Daniel Edelman, Paul S Meltzer, Christopher A Loffredo, Natsuko Hama, Tatsuhiro Shibata, Robert H Wiltrout, Curtis C Harris, Chulabhorn Mahidol, Mathuros Ruchirawat, Xin W Wang
Intrahepatic cholangiocarcinoma (ICC) and hepatocellular carcinoma (HCC) are clinically disparate primary liver cancers with etiological and biological heterogeneity. We identified common molecular subtypes linked to similar prognosis among 199 Thai ICC and HCC patients through systems integration of genomics, transcriptomics, and metabolomics. While ICC and HCC share recurrently mutated genes, including TP53, ARID1A, and ARID2, mitotic checkpoint anomalies distinguish the C1 subtype with key drivers PLK1 and ECT2, whereas the C2 subtype is linked to obesity, T cell infiltration, and bile acid metabolism...
June 6, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28647496/a-comprehensive-complex-systems-approach-to-the-study-and-analysis-of-mammalian-cell-cycle-control-system-in-the-presence-of-dna-damage-stress
#2
Ali Abroudi, Sandhya Samarasinghe, Don Kulasiri
Not many models of mammalian cell cycle system exist due to its complexity. Some models are too complex and hard to understand, while some others are too simple and not comprehensive enough. Moreover, some essential aspects, such as the response of G1-S and G2-M checkpoints to DNA damage as well as the growth factor signalling, have not been investigated from a systems point of view in current mammalian cell cycle models. To address these issues, we bring a holistic perspective to cell cycle by mathematically modelling it as a complex system consisting of important sub-systems that interact with each other...
June 21, 2017: Journal of Theoretical Biology
https://www.readbyqxmd.com/read/28646172/dacomitinib-a-pan-inhibitor-of-erbb-receptors-suppresses-growth-and-invasive-capacity-of-chemoresistant-ovarian-carcinoma-cells
#3
Majid Momeny, Ghazaleh Zarrinrad, Farima Moghaddaskho, Arash Poursheikhani, Ghazaleh Sankanian, Azam Zaghal, Shahab Mirshahvaladi, Fatemeh Esmaeili, Haniyeh Eyvani, Farinaz Barghi, Zahra Sabourinejad, Zivar Alishahi, Hassan Yousefi, Reza Ghasemi, Leila Dardaei, Davood Bashash, Bahram Chahardouli, Ahmad R Dehpour, Javad Tavakkoly-Bazzaz, Kamran Alimoghaddam, Ardeshir Ghavamzadeh, Seyed H Ghaffari
Epithelial ovarian cancer (EOC) is the most lethal gynaecological malignancy worldwide. Development of chemoresistance and peritoneal dissemination of EOC cells are the major reasons for low survival rate. Targeting signal transduction pathways which promote therapy resistance and metastatic dissemination is the key to successful treatment. Members of the ErbB family of receptors are over-expressed in EOC and play key roles in chemoresistance and invasiveness. Despite this, single-targeted ErbB inhibitors have demonstrated limited activity in chemoresistant EOC...
June 23, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28638459/towards-prognostic-profiling-of-non-small-cell-lung-cancer-new-perspectives-on-the-relevance-of-polo-like-kinase-1-expression-the-tp53-mutation-status-and-hypoxia
#4
Jolien Van den Bossche, Christophe Deben, Ken Op de Beeck, Vanessa Deschoolmeester, Christophe Hermans, Ines De Pauw, Julie Jacobs, Paul Van Schil, Jan Baptist Vermorken, Patrick Pauwels, Marc Peeters, Filip Lardon, An Wouters
Background: Currently, prognosis of non-small cell lung cancer (NSCLC) patients is based on clinicopathological factors, including TNM stage. However, there are considerable differences in patient outcome within a similar staging group, even when patients received identical treatments. In order to improve prognostic predictions and to guide treatment options, additional parameters influencing outcome are required. Polo-like kinase 1 (Plk1), a master regulator of mitotic cell division and the DNA damage response, is considered as a new potential biomarker in this research area...
2017: Journal of Cancer
https://www.readbyqxmd.com/read/28614913/the-fungal-metabolite-brefeldin-a-inhibits-dvl2-plk1-dependent-primary-cilium-disassembly
#5
Uijeong Lee, Sun-Ok Kim, Jeong-Ah Hwang, Jae-Hyuk Jang, Sangkeun Son, In-Ja Ryoo, Jong Seog Ahn, Bo Yeon Kim, Kyung Ho Lee
The primary cilium is a non-motile microtubule-based organelle that protrudes from the surface of most human cells and works as a cellular antenna to accept extracellular signals. Primary cilia assemble from the basal body during the resting stage (G0 phase) and simultaneously disassemble with cell cycle re-entry. Defective control of assembly or disassembly causes diverse human diseases including ciliopathy and cancer. To identify the effective compounds for studying primary cilium disassembly, we have screened 297 natural compounds and identified 18 and 17 primary cilium assembly and disassembly inhibitors, respectively...
June 14, 2017: Molecules and Cells
https://www.readbyqxmd.com/read/28607002/atm-wip1-activities-at-chromatin-control-plk1-re-activation-to-determine-g2-checkpoint-duration
#6
Himjyot Jaiswal, Jan Benada, Erik Müllers, Karen Akopyan, Kamila Burdova, Tobias Koolmeister, Thomas Helleday, René H Medema, Libor Macurek, Arne Lindqvist
After DNA damage, the cell cycle is arrested to avoid propagation of mutations. Arrest in G2 phase is initiated by ATM-/ATR-dependent signaling that inhibits mitosis-promoting kinases such as Plk1. At the same time, Plk1 can counteract ATR-dependent signaling and is required for eventual resumption of the cell cycle. However, what determines when Plk1 activity can resume remains unclear. Here, we use FRET-based reporters to show that a global spread of ATM activity on chromatin and phosphorylation of ATM targets including KAP1 control Plk1 re-activation...
June 12, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28600475/dual-inhibition-of-hdac-and-tyrosine-kinase-signaling-pathways-with-cudc-907-inhibits-thyroid-cancer-growth-and-metastases
#7
Shweta Kotian, Lisa Zhang, Myriem Boufraqech, Kelli Gaskins, Sudheer Kumar Gara, Martha M Quezado, Naris Nilubol, Electron Kebebew
PURPOSE: There is currently no standard therapy for anaplastic thyroid cancer (ATC) and poorly differentiated thyroid cancer (PDTC), which account for two-thirds of thyroid cancer deaths. Driver mutations in the PI3K/AKT and RAF/RAS/MEK/ERK pathways are common in ATC and PDTC. Histone deacetylases (HDACs) regulate cancer initiation and progression. Our aim was to determine the therapeutic efficacy of simultaneously targeting these pathways in thyroid cancer with a single agent, and to evaluate biomarkers of treatment response...
June 9, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28596815/next-generation-sequencing-traces-human-induced-pluripotent-stem-cell-lines-clonally-generated-from-heterogeneous-cancer-tissue
#8
Tetsuya Ishikawa
AIM: To investigate genotype variation among induced pluripotent stem cell (iPSC) lines that were clonally generated from heterogeneous colon cancer tissues using next-generation sequencing. METHODS: Human iPSC lines were clonally established by selecting independent single colonies expanded from heterogeneous primary cells of S-shaped colon cancer tissues by retroviral gene transfer (OCT3/4, SOX2, and KLF4). The ten iPSC lines, their starting cancer tissues, and the matched adjacent non-cancerous tissues were analyzed using next-generation sequencing and bioinformatics analysis using the human reference genome hg19...
May 26, 2017: World Journal of Stem Cells
https://www.readbyqxmd.com/read/28591578/plk1-activation-in-late-g2-sets-up-commitment-to-mitosis
#9
Lilia Gheghiani, Damarys Loew, Bérangère Lombard, Jörg Mansfeld, Olivier Gavet
Commitment to mitosis must be tightly coordinated with DNA replication to preserve genome integrity. While we have previously established that the timely activation of CyclinB1-Cdk1 in late G2 triggers mitotic entry, the upstream regulatory mechanisms remain unclear. Here, we report that Polo-like kinase 1 (Plk1) is required for entry into mitosis during an unperturbed cell cycle and is rapidly activated shortly before CyclinB1-Cdk1. We determine that Plk1 associates with the Cdc25C1 phosphatase and induces its phosphorylation before mitotic entry...
June 6, 2017: Cell Reports
https://www.readbyqxmd.com/read/28586718/discovery-of-a-series-of-dihydroquinoxalin-2-1h-ones-as-selective-bet-inhibitors-from-a-dual-plk1-brd4-inhibitor
#10
Jianping Hu, Yingqing Wang, Yanlian Li, Lin Xu, Danyan Cao, ShanShan Song, Mohammadali Soleimani Damaneh, Xin Wang, Tao Meng, Yue-Lei Chen, Jingkang Shen, Zehong Miao, Bing Xiong
Recent years have seen much effort to discover new chemotypes of BRD4 inhibitors. Interestingly, some kinase inhibitors have been demonstrated to be potent bromodomain inhibitors, especially the PLK1 inhibitor BI-2536 and the JAK2 inhibitor TG101209, which can bind to BRD4 with IC50 values of 0.025 μM and 0.13 μM, respectively. Although the concept of dual inhibition is intriguing, selective BRD4 inhibitors are preferred as they may diminish off-target effects and provide more flexibility in anticancer drug combination therapy...
May 27, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28575857/targeting-plk1-as-a-novel-chemopreventive-approach-to-eradicate-preneoplastic-mucosal-changes-in-the-head-and-neck
#11
D Vicky de Boer, Sanne R Martens-de Kemp, Marijke Buijze, Marijke Stigter-van Walsum, Elisabeth Bloemena, Ralf Dietrich, C René Leemans, Victor W van Beusechem, Boudewijn J M Braakhuis, Ruud H Brakenhoff
Head and neck squamous cell carcinomas (HNSCC) and local relapses thereof develop in preneoplastic fields in the mucosal linings of the upper aerodigestive tract. These fields are characterized by tumor-associated genetic changes, are frequently dysplastic and occasionally macroscopically visible. Currently, no adequate treatment options exist to prevent tumor development. Array-based screening with a panel of tumor-lethal small interfering RNAs (siRNAs) identified Polo-like kinase 1 (PLK1) as essential for survival of preneoplastic cells...
May 16, 2017: Oncotarget
https://www.readbyqxmd.com/read/28575671/structural-basis-for-mitotic-centrosome-assembly-in-flies
#12
Zhe Feng, Anna Caballe, Alan Wainman, Steven Johnson, Andreas F M Haensele, Matthew A Cottee, Paul T Conduit, Susan M Lea, Jordan W Raff
In flies, Centrosomin (Cnn) forms a phosphorylation-dependent scaffold that recruits proteins to the mitotic centrosome, but how Cnn assembles into a scaffold is unclear. We show that scaffold assembly requires conserved leucine zipper (LZ) and Cnn-motif 2 (CM2) domains that co-assemble into a 2:2 complex in vitro. We solve the crystal structure of the LZ:CM2 complex, revealing that both proteins form helical dimers that assemble into an unusual tetramer. A slightly longer version of the LZ can form micron-scale structures with CM2, whose assembly is stimulated by Plk1 phosphorylation in vitro...
June 1, 2017: Cell
https://www.readbyqxmd.com/read/28557434/dual-targeting-of-wee1-and-plk1-by-azd1775-elicits-single-agent-cellular-anticancer-activity
#13
Gabriela Wright, Volha Golubeva, Lily L Remsing Rix, Norbert Berndt, Yunting Luo, Grace A Ward, Jhanelle E Gray, Ernst Schonbrunn, Harshani R Lawrence, Alvaro N A Monteiro, Uwe Rix
Inhibition of the WEE1 tyrosine kinase enhances anticancer chemotherapy efficacy. Accordingly, the WEE1 inhibitor AZD1775 (previously MK-1775) is currently under evaluation in clinical trials for cancer in combination with chemotherapy. AZD1775 has been reported to display high selectivity and is therefore used in many studies as a probe to interrogate WEE1 biology. However, AZD1775 also exhibits anticancer activity as a single agent although the underlying mechanism is not fully understood. Using a chemical proteomics approach, we here describe a proteome-wide survey of AZD1775 targets in lung cancer cells and identify several previously unknown targets in addition to WEE1...
June 7, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28556483/drug-sensitivity-and-resistance-testing-identifies-plk1-inhibitors-and-gemcitabine-as-potent-drugs-for-malignant-peripheral-nerve-sheath-tumors-mpnst
#14
Matthias Kolberg, Jarle Bruun, Astrid Murumägi, John P Mpindi, Christian H Bergsland, Maren Høland, Ina A Eilertsen, Stine A Danielsen, Olli Kallioniemi, Ragnhild A Lothe
Patients with malignant peripheral nerve sheath tumor (MPNST), a rare soft tissue cancer associated with loss of the tumor suppressor neurofibromin (NF1), have poor prognosis and typically respond poorly to adjuvant therapy. We evaluated the effect of 299 clinical and investigational compounds on seven MPNST cell lines, two primary cultures of human Schwann cells, and five normal bone marrow aspirates, to identify potent drugs for MPNST treatment with few side effects. Top hits included Polo-like kinase 1 (PLK1) inhibitors (volasertib and BI2536) and the fluoronucleoside gemcitabine, which were validated in orthogonal assays measuring viability, cytotoxicity and apoptosis...
May 29, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/28521657/several-inhibitors-of-the-plk1-polo-box-domain-turn-out-to-be-non-specific-protein-alkylators
#15
Vincent Archambault, Karine Normandin
For almost a decade, there has been much interest in the development of chemical inhibitors of Polo-like kinase 1 (Plk1) protein interactions. Plk1 is a master regulator of the cell division cycle that controls numerous substrates. It is a promising target for cancer drug development. Inhibitors of the kinase domain of Plk1 had some success in clinical trials. However, they are not perfectly selective. In principle, Plk1 can also be inhibited by interfering with its protein interaction domain, the Polo-Box Domain (PBD)...
May 19, 2017: Cell Cycle
https://www.readbyqxmd.com/read/28512243/plk1-phosphorylation-of-mre11-antagonizes-the-dna-damage-response
#16
Zhiguo Li, Jie Li, Yifan Kong, Shan Yan, Nihal Ahmad, Xiaoqi Liu
The mitotic kinase Plk1 contributes to the DNA damage response (DDR) by targeting multiple factors downstream of the core responder kinase ATM/ATR. In this study, we show that Polo-like kinase 1 (Plk1) also phosphorylates key factors upstream of ATM/ATR and regulates their DDR-related functions. Plk1 phosphorylated Mre11, a component of the Mre11/Rad50/Nbs1 (MRN) complex, at serine 649 (S649) during DDR. Phosphorylation of Mre11-S649 by Plk1 primed subsequent CK2-mediated phosphorylation at Mre11-serine 688 (S688)...
May 16, 2017: Cancer Research
https://www.readbyqxmd.com/read/28504248/the-flavonoid-tl-2-8-induces-cell-death-and-immature-mitophagy-in-breast-cancer-cells-via-abrogating-the-function-of-the-aha1-hsp90-complex
#17
Hui-Juan Liu, Xiao-Xiao Jiang, Yi-Zhen Guo, Fang-Hui Sun, Xin-Hui Kou, Yong Bao, Zhu-Qing Zhang, Zhao-Hu Lin, Ting-Bo Ding, Lan Jiang, Xin-Sheng Lei, Yong-Hua Yang
The flavonoid quercetin exhibits significant anticancer activities with few side effects. In the current study, we characterized TL-2-8, a quercetin derivative, as a novel anticancer agent in vitro and in vivo. Cell proliferation and viability were assessed using Cell Counting Kit-8 and CellTiter-Blue assay, respectively. Cell death was examined using PI staining or a TUNEL assay. Mitophagy was determined by measuring autophagic flux and by confocal imaging. Protein expression was examined by Western blotting...
May 1, 2017: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/28499276/augmented-expression-of-polo-like-kinase-1-indicates-poor-clinical-outcome-for-breast-patients-a-systematic-review-and-meta-analysis
#18
REVIEW
Yunfeng Zhang, Zhibin Wu, Dapeng Liu, Meng Wang, Guodong Xiao, Peili Wang, Xin Sun, Hong Ren, Shou-Ching Tang, Ning Du
Polo-like kinases 1 (PLK1), a key regulator of mitosis, plays an essential role in maintaining genomic stability. Up-regulation of PLK1 was found in tumorigenesis and tumor progression of diverse cancers. However, the clinicopathological and prognostic implications of PLK1 in breast cancer (BC) have yet to be unveiled. Therefore, using PubMed, Web of Science, Embase, and Chinese databases, we conducted a meta-analysis to define the potential clinical value of PLK1 in BC. Eleven eligible articles with 2481 patients enrolled were included in the present meta-analysis, of which eight studies reported on the relationship between PLK1 expression and clinicopathological features, and nine studies provided survival data in BC patients...
April 20, 2017: Oncotarget
https://www.readbyqxmd.com/read/28487115/lncrna-hoxd-as1-regulates-proliferation-and-chemo-resistance-of-castration-resistant-prostate-cancer-via-recruiting-wdr5
#19
Peng Gu, Xu Chen, Ruihui Xie, Jinli Han, Weibin Xie, Bo Wang, Wen Dong, Changhao Chen, Meihua Yang, Junyi Jiang, Ziyue Chen, Jian Huang, Tianxin Lin
Castration-resistant prostate cancer (CRPC) that occurs after the failure of androgen deprivation therapy is the leading cause of deaths in prostate cancer patients. Thus, there is an obvious and urgent need to fully understand the mechanism of CRPC and discover novel therapeutic targets. Long noncoding RNAs (lncRNAs) are crucial regulators in many human cancers, yet their potential roles and molecular mechanisms in CRPC are poorly understood. In this study, we discovered that an lncRNA HOXD-AS1 is highly expressed in CRPC cells and correlated closely with Gleason score, T stage, lymph nodes metastasis, and progression-free survival...
May 6, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28482026/pre-clinical-drug-screen-reveals-topotecan-actinomycin-d-and-volasertib-as-potential-new-therapeutic-candidates-for-etmr-brain-tumor-patients
#20
Christin Schmidt, Nil A Schubert, Sebastian Brabetz, Norman Mack, Benjamin Schwalm, Jennifer A Chan, Florian Selt, Christel Herold-Mende, Olaf Witt, Till Milde, Stefan M Pfister, Andrey Korshunov, Marcel Kool
Background: Embryonal tumor with multilayered rosettes (ETMR) is a rare and aggressive embryonal brain tumor that solely occurs in infants and young children and has only recently been recognized as a separate brain tumor entity in the WHO classification for CNS tumors. Patients have a very dismal prognosis with a median survival of 12 months upon diagnosis despite aggressive treatment. The aim of this study was to develop novel treatment regimens in a pre-clinical drug screen in order to inform potentially more active clinical trial protocols...
May 8, 2017: Neuro-oncology
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