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Polo-like kinase

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https://www.readbyqxmd.com/read/29443884/linear-regression-qsar-models-for-polo-like-kinase-1-inhibitors
#1
Pablo R Duchowicz
A structurally diverse dataset of 530 polo-like kinase-1 (PLK1) inhibitors is compiled from the ChEMBL database and studied by means of a conformation-independent quantitative structure-activity relationship (QSAR) approach. A large number (26,761) of molecular descriptors are explored with the main intention of capturing the most relevant structural characteristics affecting the bioactivity. The structural descriptors are derived with different freeware, such as PaDEL, Mold², and QuBiLs-MAS; such descriptor software complements each other and improves the QSAR results...
February 14, 2018: Cells
https://www.readbyqxmd.com/read/29437878/essential-role-of-polo-like-kinase-1-plk1-oncogene-in-tumor-growth-and-metastasis-of-tamoxifen-resistant-breast-cancer
#2
Sung Baek Jeong, Ji Hye Im, Jeong-Hoon Yoon, Quyen Thu Bui, Sung Chul Lim, Joon Myong Song, Yumi Shim, Jieun Yun, Janghee Hong, Keon Wook Kang
The most common therapy for estrogen receptor-positive breast cancer is anti-hormone therapy such as tamoxifen (TAM). However, acquisition of resistance to TAM in one-third of patients presents a serious clinical problem. Polo-like kinase 1 (Plk1) is a key oncogenic regulator of completion of G2/M phase of the cell cycle. We assessed Plk1 expression in five chemoresistant cancer cell types and found that Plk1 and its downstream phosphatase Cdc25c were selectively overexpressed in TAM-resistant MCF-7 (TAMR-MCF-7) breast cancer cells...
February 7, 2018: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29434041/polo-like-kinase-4-inhibition-produces-polyploidy-and-apoptotic-death-of-lung-cancers
#3
Masanori Kawakami, Lisa Maria Mustachio, Lin Zheng, Yulong Chen, Jaime Rodriguez-Canales, Barbara Mino, Jonathan M Kurie, Jason Roszik, Pamela Andrea Villalobos, Kelsie L Thu, Jennifer Silvester, David W Cescon, Ignacio I Wistuba, Tak W Mak, Xi Liu, Ethan Dmitrovsky
Polo-like kinase 4 (PLK4) is a serine/threonine kinase regulating centriole duplication. CFI-400945 is a highly selective PLK4 inhibitor that deregulates centriole duplication, causing mitotic defects and death of aneuploid cancers. Prior work was substantially extended by showing CFI-400945 causes polyploidy, growth inhibition, and apoptotic death of murine and human lung cancer cells, despite expression of mutated KRAS or p53. Analysis of DNA content by propidium iodide (PI) staining revealed cells with >4N DNA content (polyploidy) markedly increased after CFI-400945 treatment...
February 6, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29433555/sf3b1-deficiency-impairs-human-erythropoiesis-via-activation-of-p53-pathway-implications-for-understanding-of-ineffective-erythropoiesis-in-mds
#4
Yumin Huang, John Hale, Yaomei Wang, Wei Li, Shijie Zhang, Jieying Zhang, Huizhi Zhao, Xinhua Guo, Jing Liu, Hongxia Yan, Karina Yazdanbakhsh, Gang Huang, Christopher D Hillyer, Narla Mohandas, Lixiang Chen, Ling Sun, Xiuli An
BACKGROUND: SF3B1 is a core component of splicing machinery. Mutations in SF3B1 are frequently found in myelodysplastic syndromes (MDS), particularly in patients with refractory anemia with ringed sideroblasts (RARS), characterized by isolated anemia. SF3B1 mutations have been implicated in the pathophysiology of RARS; however, the physiological function of SF3B1 in erythropoiesis remains unknown. METHODS: shRNA-mediated approach was used to knockdown SF3B1 in human CD34 + cells...
February 12, 2018: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/29429933/npas4-is-a-critical-regulator-of-learning-induced-plasticity-at-mossy-fiber-ca3-synapses-during-contextual-memory-formation
#5
Feng-Ju Weng, Rodrigo I Garcia, Stefano Lutzu, Karina Alviña, Yuxiang Zhang, Margaret Dushko, Taeyun Ku, Khaled Zemoura, David Rich, Dario Garcia-Dominguez, Matthew Hung, Tushar D Yelhekar, Andreas Toft Sørensen, Weifeng Xu, Kwanghun Chung, Pablo E Castillo, Yingxi Lin
Synaptic connections between hippocampal mossy fibers (MFs) and CA3 pyramidal neurons are essential for contextual memory encoding, but the molecular mechanisms regulating MF-CA3 synapses during memory formation and the exact nature of this regulation are poorly understood. Here we report that the activity-dependent transcription factor Npas4 selectively regulates the structure and strength of MF-CA3 synapses by restricting the number of their functional synaptic contacts without affecting the other synaptic inputs onto CA3 pyramidal neurons...
January 29, 2018: Neuron
https://www.readbyqxmd.com/read/29423069/combined-effects-of-plk1-and-ras-in-hepatocellular-carcinoma-reveal-rigosertib-as-promising-novel-therapeutic-dual-hit-option
#6
Peter Dietrich, Kim Freese, Abdo Mahli, Wolfgang Erwin Thasler, Claus Hellerbrand, Anja Katrin Bosserhoff
Inhibition of RAS-RAF-ERK-signaling is a major mechanism mediated by the multi-kinase inhibitors sorafenib and regorafenib, the only effective therapeutic approaches for advanced hepatocellular carcinoma (HCC). This underlines the importance of RAS-RAF-ERK-signaling in HCC. Most RAS isoforms were not yet described to play crucial roles in HCC. However, several studies indicate that the HRAS isoform can function as potent oncogene in HCC, but pharmacologic RAS inhibition has not yet been investigated. Moreover, the cell cycle promoting polo-like kinase 1 (PLK1) is an increasingly recognized therapeutic target in HCC that can be activated by RAS-RAF-signaling...
January 9, 2018: Oncotarget
https://www.readbyqxmd.com/read/29416714/mitosis-specific-phosphorylation-of-mis18%C3%AE-by-aurora-b-kinase-enhances-kinetochore-recruitment-of-polo-like-kinase-1
#7
Minkyoung Lee, Ik Soo Kim, Koog Chan Park, Jong-Seo Kim, Sung Hee Baek, Keun Il Kim
Mis18α, a component of Mis18 complex comprising of Mis18α, Mis18β, and M18BP1, is known to localize at the centromere from late telophase to early G1 phase and plays a priming role in CENP-A deposition. Although its role in CENP-A deposition is well established, the other function of Mis18α remains unknown. Here, we elucidate a new function of Mis18α that is critical for the proper progression of cell cycle independent of its role in CENP-A deposition. We find that Aurora B kinase phosphorylates Mis18α during mitosis not affecting neither centromere localization of Mis18 complex nor centromere loading of CENP-A...
January 5, 2018: Oncotarget
https://www.readbyqxmd.com/read/29402316/antitumor-activity-of-the-polo-like-kinase-inhibitor-tak-960-against-preclinical-models-of-colorectal-cancer
#8
Peter J Klauck, Stacey M Bagby, Anna Capasso, Erica L Bradshaw-Pierce, Heather M Selby, Anna Spreafico, John J Tentler, Aik Choon Tan, Jihye Kim, John J Arcaroli, Alicia Purkey, Wells A Messersmith, Keisuke Kuida, S Gail Eckhardt, Todd M Pitts
BACKGROUND: Polo-like kinase 1 (Plk1) is a serine/threonine kinase that is a key regulator of multiple stages of mitotic progression. Plk1 is upregulated in many tumor types including colorectal cancer (CRC) and portends a poor prognosis. TAK-960 is an ATP-competitive Plk1 inhibitor that has demonstrated efficacy across a broad range of cancer cell lines, including CRC. In this study, we investigated the activity of TAK-960 against a large collection of CRC models including 55 cell lines and 18 patient-derived xenografts...
February 5, 2018: BMC Cancer
https://www.readbyqxmd.com/read/29393385/bi2536-a-potent-and-selective-inhibitor-of-polo-like-kinase-1-in-combination-with-cisplatin-exerts-synergistic-effects-on-gastric-cancer-cells
#9
Guodong Lian, Leping Li, Yulong Shi, Changqing Jing, Jinglei Liu, Xiaobo Guo, Qingqing Zhang, Tianyu Dai, Fei Ye, Yanyan Wang, Man Chen
BI2536 is a highly selective and potent inhibitor of polo-like kinase 1 (PLK1). In this study, we aimed to determine whether BI2536 and cisplatin can synergistically inhibit the malignant behavior of gastric cancer cells. For this purpose, the expression of PLK1 in gastric cancer cells was determined. The effects of BI2536, cisplatin, and the combination of BI2536 and cisplatin on gastric cancer cell viability, invasion, cell cycle arrest and apoptosis were assessed. Furthermore, the expression of cell cycle-regulated proteins was examined...
January 25, 2018: International Journal of Oncology
https://www.readbyqxmd.com/read/29391599/targeting-plk1-overcomes-t-dm1-resistance-via-cdk1-dependent-phosphorylation-and-inactivation-of-bcl-2-xl-in-her2-positive-breast-cancer
#10
Özge Saatci, Simone Borgoni, Özge Akbulut, Selvi Durmuş, Umar Raza, Erol Eyüpoğlu, Can Alkan, Aytekin Akyol, Özgür Kütük, Stefan Wiemann, Özgür Şahin
Trastuzumab-refractory, HER2 (human epidermal growth factor receptor 2)-positive breast cancer is commonly treated with trastuzumab emtansine (T-DM1), an antibody-drug conjugate of trastuzumab and the microtubule-targeting agent, DM1. However, drug response reduces greatly over time due to acquisition of resistance whose molecular mechanisms are mostly unknown. Here, we uncovered a novel mechanism of resistance against T-DM1 by combining whole transcriptome sequencing (RNA-Seq), proteomics and a targeted small interfering RNA (siRNA) sensitization screen for molecular level analysis of acquired and de novo T-DM1-resistant models of HER2-overexpressing breast cancer...
February 2, 2018: Oncogene
https://www.readbyqxmd.com/read/29388912/multiple-kinases-inhibit-origin-licensing-and-helicase-activation-to-ensure-reductive-cell-division-during-meiosis
#11
David V Phizicky, Luke E Berchowitz, Stephen P Bell
Meiotic cells undergo a single round of DNA replication followed by two rounds of chromosome segregation (the meiotic divisions) to produce haploid gametes. Both DNA replication and chromosome segregation are similarly regulated by CDK oscillations in mitotic cells. Yet how these two events are uncoupled between the meiotic divisions is unclear. Using Saccharomyces cerevisiae, we show that meiotic cells inhibit both helicase loading and helicase activation to prevent DNA replication between the meiotic divisions...
February 1, 2018: ELife
https://www.readbyqxmd.com/read/29383095/polo-like-kinase-1-plk-1-and-c-myc-inhibition-with-the-dual-kinase-bromodomain-inhibitor-volasertib-in-aggressive-lymphomas
#12
Carlos Murga-Zamalloa, Avery Polk, Walter Hanel, Pinki Chowdhury, Noah Brown, Alexandra C Hristov, Nathanael G Bailey, Tianjiao Wang, Tycel Phillips, Sumana Devata, Pradeep Poonnen, Juan Gomez-Gelvez, Kedar V Inamdar, Ryan A Wilcox
Survival following anthracycline-based chemotherapy remains poor among patients with most T-cell lymphoproliferative disorders. This may be attributed, at least in part, to cell-autonomous mechanisms of chemotherapy resistance observed in these lymphomas, including the loss of important tumor suppressors and the activation of signaling cascades that culminate in the expression and activation of transcription factors promoting cell growth and survival. Therefore, the identification of novel therapeutic targets is needed...
December 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/29366414/the-acidophilic-kinases-plk2-and-plk3-structure-substrate-targeting-and-inhibition
#13
Giorgio Cozza, Mauro Salvi
PLK2 and PLK3 are two closely related acidophilic kinases belonging to the Polo-like kinases (PLKs), a family of five members in mammals with a central role in cell cycle and related events. PLK1 is the most investigated enzyme from both physiological and pharmaceutical points of view, however, several specialized cellular functions of PLK2 and PLK3 have been recently discovered paving the way to deepened studies on their biological roles and their feasible selection as future therapeutic targets. Our review aims to provide a summarized view of the current knowledge regarding PLK2 and PLK3 kinases, including substrate specificity and signaling pathways directly affected by these kinases...
January 23, 2018: Current Protein & Peptide Science
https://www.readbyqxmd.com/read/29352113/polo-like-kinase-4-mediates-epithelial-mesenchymal-transition-in-neuroblastoma-via-pi3k-akt-signaling-pathway
#14
Xiangdong Tian, Dejun Zhou, Lu Chen, Yao Tian, Benfu Zhong, Yanna Cao, Qiuping Dong, Meng Zhou, Jie Yan, Yalei Wang, Yanli Qiu, Lianmin Zhang, Zhongyuan Li, Huijuan Wang, Daowei Wang, Guoguang Ying, Qiang Zhao
Neuroblastoma (NB) is the most common malignant tumor in infancy and most common extracranial solid tumor in childhood. With the improvement of diagnosis and treatment, the survival rate of patients with low-risk and intermediate-risk NB can reach up to 90%. In contrast, for high-risk NBs, the long-term survival rate is still <40% because of heterogeneity of this tumor. The pathogenesis of NB is still not explicit, therefore it is of great significance to explore the mechanism of NB tumorigenesis and discover new therapeutic targets for NB...
January 19, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29348559/plk1-protects-against-sepsis-induced-intestinal-barrier-dysfunction
#15
Yingya Cao, Qun Chen, Zhen Wang, Tao Yu, Jingyi Wu, Xiaogan Jiang, Xiaoju Jin, Weihua Lu
Sepsis and sepsis-associated intestinal barrier dysfunction are common in intensive care units, with high mortality. The aim of this study is to investigate whether Polo-like kinase 1 (PLK1) ameliorates sepsis-induced intestinal barrier dysfunction in the intestinal epithelium. The mouse intestinal barrier was disrupted after Lipopolysaccharide (LPS) injection due to intestinal epithelial cell apoptosis and proliferation inhibition, accompanied by decreased PLK1. In HT-29 intestinal epithelial cells, LPS stimulation induced cell apoptosis and inhibited cell proliferation...
January 18, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29340047/inhibition-of-polo-like-kinase-4-plk4-a-new-therapeutic-option-for-rhabdoid-tumors-and-pediatric-medulloblastoma
#16
Simone Treiger Sredni, Anders W Bailey, Amreena Suri, Rintaro Hashizume, Xingyao He, Nundia Louis, Tufan Gokirmak, David R Piper, Daniel M Watterson, Tadanori Tomita
Rhabdoid tumors (RT) are highly aggressive and vastly unresponsive embryonal tumors. They are the most common malignant CNS tumors in infants below 6 months of age. Medulloblastomas (MB) are embryonal tumors that arise in the cerebellum and are the most frequent pediatric malignant brain tumors. Despite the advances in recent years, especially for the most favorable molecular subtypes of MB, the prognosis of patients with embryonal tumors remains modest with treatment related toxicity dreadfully high. Therefore, new targeted therapies are needed...
December 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/29339720/plumbagin-inhibits-the-proliferation-and-survival-of-esophageal-cancer-cells-by-blocking-stat3-plk1-akt-signaling
#17
Ying-Ya Cao, Jing Yu, Ting-Ting Liu, Kai-Xia Yang, Li-Yan Yang, Qun Chen, Feng Shi, Jia-Jie Hao, Yan Cai, Ming-Rong Wang, Wei-Hua Lu, Yu Zhang
Esophageal squamous cell carcinoma (ESCC) is one of the deadliest cancers, and it requires novel treatment approaches and effective drugs. In the present study, we found that treatment with plumbagin, a natural compound, reduced proliferation and survival of the KYSE150 and KYSE450 ESCC cell lines in a dose-dependent manner in vitro. The drug also effectively inhibited the viability of primary ESCC cells from fresh biopsy specimens. Furthermore, plumbagin-induced mitotic arrest and massive apoptosis in ESCC cells...
January 16, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29339188/the-enhancement-of-siplk1-penetration-across-bbb-and-its-anti-glioblastoma-activity-in-vivo-by-magnet-and-transferrin-co-modified-nanoparticle
#18
Dao-Zhou Liu, Ying Cheng, Rong-Qiao Cai, Wen-Wen Wang, Han Cui, Miao Liu, Bang-le Zhang, Qi-Bing Mei, Si-Yuan Zhou
In order to enhance the penetration of small interference RNA against the polo-like kinase I (siPLK1) across BBB to treat glioblastoma (GBM), transferrin (Tf) modified magnetic nanoparticle (Tf-PEG-PLL/MNP@siPLK1) was prepared. The in vitro experiments indicated that Tf-PEG-PLL/MNP@siPLK1 enhanced the cellular uptake of siPLK1, which resulted in an increase of gene silencing effect and cytotoxicity of Tf-PEG-PLL/MNP@siPLK1 on U87 cells. Besides, Tf-PEG-PLL/MNP@siPLK1 significantly inhibited the growth of U87 glioblastoma spheroids and markedly increased the BBB penetration efficiency of siPLK1 with the application of external magnetic field in in-vitro BBB model...
January 12, 2018: Nanomedicine: Nanotechnology, Biology, and Medicine
https://www.readbyqxmd.com/read/29331044/journey-of-oocyte-from-metaphase-i-to-metaphase-ii-stage-in-mammals
#19
Alka Sharma, Meenakshi Tiwari, Anumegha Gupta, Ashutosh N Pandey, Pramod K Yadav, Shail K Chaube
In mammals, journey from metaphase-I (M-I) to metaphase-II (M-II) is important since oocyte extrude first polar body (PB-I) and gets converted into haploid gamete. The molecular and cellular changes associated with meiotic cell cycle progression from M-I to M-II stage and extrusion of PB-I remain ill understood. Several factors drive oocyte meiosis from M-I to M-II stage. The mitogen-activated protein kinase3/1 (MAPK3/1), signal molecules and Rho family GTPases act through various pathways to drive cell cycle progression from M-I to M-II stage...
January 13, 2018: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/29330283/centriole-overduplication-is-the-predominant-mechanism-leading-to-centrosome-amplification-in-melanoma
#20
Ryan A Denu, Maria Shabbir, Minakshi Nihal, Chandra K Singh, B Jack Longley, Mark E Burkard, Nihal Ahmad
Centrosome amplification (CA) is common in cancer and can arise by centriole overduplication or by cell doubling events, including the failure of cell division and cell-cell fusion. To assess the relative contributions of these two mechanisms, the number of centrosomes with mature/mother centrioles was examined by immunofluorescence in a tissue microarray of human melanomas and benign nevi ( n = 79 and 17, respectively). The centrosomal protein 170 (CEP170) was used to identify centrosomes with mature centrioles; this is expected to be present in most centrosomes with cell doubling, but on fewer centrosomes with overduplication...
January 12, 2018: Molecular Cancer Research: MCR
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