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https://www.readbyqxmd.com/read/28920432/plk1-targeted-fluorescent-tumor-imaging-with-high-signal-background-ratio
#1
Ji-Ting Hou, Kyung-Phil Ko, Hu Shi, Wen Xiu Ren, Peter Verwilst, Seyoung Koo, Jin Yong Lee, Sung-Gil Chi, Jong Seung Kim
As significantly expressed during cell division, polo-like kinase 1 (PLK1) plays crucial roles in numerous mitotic events and has attracted interest as a potential therapeutic marker in oncological drug discovery. We prepared two small molecular fluorescent probes, 1 and 2, conjugated to SBE13 (a type II PLK1 inhibitor) to investigate the PLK1-targeted imaging of cancer cells and tumors. Enzymatic docking studies, molecular dynamics simulations, in vitro and in vivo imaging experiments, all supported the selective targeting and visualization of PLK1 expressing cells by probes 1 and 2, and probe 2 was successfully demonstrated to image PLK1-upregualted tumors with a remarkable signal to background ratios...
September 18, 2017: ACS Sensors
https://www.readbyqxmd.com/read/28915707/augmented-expression-of-polo-like-kinase-1-indicates-poor-clinical-outcome-for-breast-patients-a-systematic-review-and-meta-analysis
#2
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...
August 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28900036/polo-like-kinase-1-plk1-overexpression-enhances-ionizing-radiation-induced-cancer-formation-in-mice
#3
Zhiguo Li, Jinghui Liu, Jie Li, Yifan Kong, George Sandusky, Xi Rao, Yunlong Liu, Jun Wan, Xiaoqi Liu
Polo-like kinase 1 (Plk1), a serine/threonine protein kinase normally expressed in mitosis, is frequently upregulated in multiple types of human tumors regardless of the cell cycle stage. However, the causal relationship between Plk1 upregulation and tumorigenesis is incompletely investigated. To this end, using a conditional expression system, here we generated Plk1 transgenic mouse lines to examine Plk1 role in tumorigenesis. Plk1 overexpression in mouse embryonic fibroblasts prepared from the transgenic mice led to aberrant mitosis followed by aneuploidy and apoptosis...
September 12, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28887496/differential-gene-expression-profiling-linked-to-tumor-progression-of-splenic-marginal-zone-lymphoma
#4
Tomonori Higuchi, Yumiko Hashida, Ayuko Taniguchi, Mikio Kamioka, Masanori Daibata
The genetic events that lead to aggressive transformation of cases of splenic marginal zone lymphoma (SMZL) after the chronic clinical stage have not been well understood. We aimed to find candidate genes associated with aggressive features of SMZL. We have successfully established two SMZL cell lines, designated SL-15 and SL-22, derived from the same patient's tumor clone in chronic and aggressive phases, respectively. Microarray analysis identified cell cycle-associated genes-specifically PLK1-as the most significantly upregulated in primary aggressive SMZL cells compared with cells from chronic phase...
September 8, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28881742/eribulin-alone-or-in-combination-with-the-plk1-inhibitor-bi-6727-triggers-intrinsic-apoptosis-in-ewing-sarcoma-cell-lines
#5
Lilly Magdalena WeiΔ, Manuela Hugle, Simone Fulda
In this study, we investigated the molecular mechanisms of eribulin-induced cell death and its therapeutic potential in combination with the PLK1 inhibitor BI 6727 in Ewing sarcoma (ES). Here, we show that eribulin triggers cell death in a dose-dependent manner in a panel of ES cell lines. In addition, eribulin at subtoxic, low nanomolar concentrations acts in concert with BI 6727 to induce cell death and to suppress long-term clonogenic survival. Mechanistic studies reveal that eribulin monotherapy at cytotoxic concentrations and co-treatment with eribulin at subtoxic concentrations together with BI 6727 arrest cells in the M phase of the cell cycle prior to the onset of cell death...
August 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/28867728/development-of-a-high-throughput-assay-for-inhibitors-of-the-polo-box-domain-of-polo-like-kinase-1-based-on-time-resolved-fluorescence-energy-transfer
#6
Tae Gi Kim, Ju Hee Lee, Mi Young Lee, Ka-Ul Kim, Jeong Hyun Lee, Chi Hoon Park, Byung Ho Lee, Kwang-Seok Oh
Although enzyme-linked immunosorbent assay (ELISA) technology has been widely accepted for binding assays against the polo-box domain (PBD) of polo-like kinase-1 (Plk1), these assays have a limitation-related heterogeneous procedure, such as multiple incubations and washing steps to apply high-throughput screenings (HTSs). In the present study, a Plk1-PBD binding assay based on time-resolved fluorescence energy transfer (TR-FRET) was developed for HTS of PBD-binding inhibitors. The TR-FRET-based Plk1-PBD binding assay is sensitive and robust and can be miniaturized into the 384-well plate-based format...
2017: Biological & Pharmaceutical Bulletin
https://www.readbyqxmd.com/read/28861165/association-of-ecrg4-with-plk1-cdk4-plod1-and-plod2-in-esophageal-squamous-cell-carcinoma
#7
Linwei Li, Wenyu Wang, Xiaoyan Li, Tianhui Gao
Esophageal cancer-related gene 4 (ECRG4) is a tumor suppressor gene associated with the prognosis of esophageal squamous-cell carcinoma (ESCC). Studies have reported that ECRG4 effectively inhibits the proliferation, migration and invasion of ESCC cells. In the current study, ectopic expression of ECRG4 significantly induced ESCC cell apoptosis. To further understand the molecular profile of ECRG4 overexpression in ESCC cells, tandem mass tag (TMT) labeling followed by LC-MS/MS analysis was applied on samples from ECRG4 overexpressed cells and control cells...
2017: American Journal of Translational Research
https://www.readbyqxmd.com/read/28851945/delayed-apc-c-activation-extends-the-first-mitosis-of-mouse-embryos
#8
Anna Ajduk, Bernhard Strauss, Jonathon Pines, Magdalena Zernicka-Goetz
The correct temporal regulation of mitosis underpins genomic stability because it ensures the alignment of chromosomes on the mitotic spindle that is required for their proper segregation to the two daughter cells. Crucially, sister chromatid separation must be delayed until all the chromosomes have attached to the spindle; this is achieved by the Spindle Assembly Checkpoint (SAC) that inhibits the Anaphase Promoting Complex/Cyclosome (APC/C) ubiquitin ligase. In many species the first embryonic M-phase is significantly prolonged compared to the subsequent divisions, but the reason behind this has remained unclear...
August 29, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28851440/plk1-is-essential-for-proper-chromosome-segregation-during-meiosis-i-meiosis-ii-transition-in-pig-oocytes
#9
Zixiao Zhang, Changchao Chen, Liying Ma, Qiuchen Yu, Shuai Li, Benazir Abbasi, Jiayi Yang, Rong Rui, Shiqiang Ju
BACKGROUND: Polo-like kinase 1 (Plk1), as a characteristic regulator in meiosis, organizes multiple biological events of cell division. Although Plk1 has been implicated in various functions in somatic cell mitotic processes, considerably less is known regarding its function during the transition from metaphase I (MI) to metaphase II (MII) stage in oocyte meiotic progression. METHODS: In this study, the possible role of Plk1 during the MI-to-MII stage transition in pig oocytes was addressed...
August 29, 2017: Reproductive Biology and Endocrinology: RB&E
https://www.readbyqxmd.com/read/28843004/single-nucleotide-polymorphisms-rs911160-in-aurka-and-rs2289590-in-aurkb-mitotic-checkpoint-genes-contribute-to-gastric-cancer-susceptibility
#10
Aner Mesic, Ela Markocic, Marija Rogar, Robert Juvan, Petra Hudler, Radovan Komel
BACKGROUND: Single nucleotide polymorphisms (SNPs) in mitotic checkpoint genes could confer increased susceptibility to gastric cancer (GC). We investigated the association of Aurora kinase A (AURKA), Aurora kinase B (AURKB), Aurora kinase C (AURKC), Polo-like kinase 1 (PLK1) and Budding uninhibited by benzimidazol 3, yeast (BUB3) gene polymorphisms with GC risk. MATERIALS AND METHODS: Genotyping of 6 SNPs in AURKA (rs911160 and rs8173), AURKB (rs2289590), AURKC (rs11084490), PLK1 (rs42873), and BUB3 (rs7897156) was performed using TaqMan genotyping assays...
August 26, 2017: Environmental and Molecular Mutagenesis
https://www.readbyqxmd.com/read/28821799/plk1-bound-to-bub1-contributes-to-spindle-assembly-checkpoint-activity-during-mitosis
#11
Masanori Ikeda, Kozo Tanaka
For faithful chromosome segregation, the formation of stable kinetochore-microtubule attachment and its monitoring by the spindle assembly checkpoint (SAC) are coordinately regulated by mechanisms that are currently ill-defined. Here, we show that polo-like kinase 1 (Plk1), which is instrumental in forming stable kinetochore-microtubule attachments, is also involved in the maintenance of SAC activity by binding to Bub1, but not by binding to CLASP2 or CLIP-170. The effect of Plk1 on the SAC was found to be mediated through phosphorylation of Mps1, an essential kinase for the SAC, as well as through phosphorylation of the MELT repeats in Knl1...
August 18, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28820331/polo-like-kinase-1-plk1-dependent-phosphorylation-of-methylenetetrahydrofolate-reductase-mthfr-regulates-replication-via-histone-methylation
#12
Xueyan Li, Shanshan Nai, Yuehe Ding, Qizhi Geng, Bingtao Zhu, Kai Yu, Wei-Guo Zhu, Meng-Qiu Dong, Xiao-Dong Su, Xingzhi Xu, Jing Li
Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme regulating the folate cycle and its genetic variations have been associated with various human diseases. Previously we identified that MTHFR is phosphorylated by cyclin-dependent kinase 1 (CDK1) at T34 and MTHFR underlies heterochromatin maintenance marked by H3K9me3 levels. Herein we demonstrate that pT34 creates a binding motif that docks MTHFR to the polo-binding domain (PBD) of polo-like kinase 1 (PLK1), a fundamental kinase that orchestrates many cell cycle events...
August 18, 2017: Cell Cycle
https://www.readbyqxmd.com/read/28819179/identification-of-polo-like-kinases-as-potential-novel-drug-targets-for-influenza-a-virus
#13
Marie O Pohl, Jessica von Recum-Knepper, Ariel Rodriguez-Frandsen, Caroline Lanz, Emilio Yángüez, Stephen Soonthornvacharin, Thorsten Wolff, Sumit K Chanda, Silke Stertz
In recent years genome-wide RNAi screens have revealed hundreds of cellular factors required for influenza virus infections in human cells. The long-term goal is to establish some of them as drug targets for the development of the next generation of antivirals against influenza. We found that several members of the polo-like kinases (PLK), a family of serine/threonine kinases with well-known roles in cell cycle regulation, were identified as hits in four different RNAi screens and we therefore studied their potential as drug target for influenza...
August 17, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28817632/interdependency-and-phosphorylation-of-kif4-and-condensin-i-are-essential-for-organization-of-chromosome-scaffold
#14
Rawin Poonperm, Hideaki Takata, Susumu Uchiyama, Kiichi Fukui
Kinesin family member 4 (KIF4) and condensins I and II are essential chromosomal proteins for chromosome organization by locating primarily to the chromosome scaffold. However, the mechanism of how KIF4 and condensins localize to the chromosome scaffold is poorly understood. Here, we demonstrate a close relationship between the chromosome localization of KIF4 and condensin I, but not condensin II, and show that KIF4 and condensin I assist each other for stable scaffold formation by forming a stable complex...
2017: PloS One
https://www.readbyqxmd.com/read/28807782/modulating-protein-protein-interactions-of-the-mitotic-polo-like-kinases-to-target-mutant-kras
#15
Ana J Narvaez, Suzan Ber, Alex Crooks, Amy Emery, Bryn Hardwick, Estrella Guarino Almeida, David J Huggins, David Perera, Meredith Roberts-Thomson, Roberta Azzarelli, Fiona E Hood, Ian A Prior, David W Walker, Richard Boyce, Robert G Boyle, Samuel P Barker, Christopher J Torrance, Grahame J McKenzie, Ashok R Venkitaraman
Mutations activating KRAS underlie many forms of cancer, but are refractory to therapeutic targeting. Here, we develop Poloppin, an inhibitor of protein-protein interactions via the Polo-box domain (PBD) of the mitotic Polo-like kinases (PLKs), in monotherapeutic and combination strategies to target mutant KRAS. Poloppin engages its targets in biochemical and cellular assays, triggering mitotic arrest with defective chromosome congression. Poloppin kills cells expressing mutant KRAS, selectively enhancing death in mitosis...
July 27, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28794108/plk1-regulates-spindle-association-of-phosphorylated-eukaryotic-translation-initiation-factor-4e-binding-protein-and-spindle-function-in-mouse-oocytes
#16
Ashley L Severance, Keith E Latham
Oocyte meiotic spindles are associated with spindle-enriched mRNAs, phosphorylated ribosome protein S6, and phosphorylated variants of the key translational regulator EIF4EBP1, consistent with translational control of localized mRNAs by EIF4EBP1 in facilitating spindle formation and stability. Using specific kinase inhibitors, we determined which kinases regulate phosphorylation status of EIF4EBP1 associated with meiotic spindles in mouse oocytes, and effects of kinase inhibition on chromosome congression and spindle formation...
August 9, 2017: American Journal of Physiology. Cell Physiology
https://www.readbyqxmd.com/read/28792760/structural-basis-of-wee-kinases-functionality-and-inactivation-by-diverse-small-molecule-inhibitors
#17
Jin-Yi Zhu, Rebecca Ann Duenes Cuellar, Norbert Berndt, Hee Eun Lee, Sanne H Olesen, Mathew P Martin, Jeffrey T Jensen, Gunda I Georg, Ernst Schönbrunn
Members of the Wee family of kinases negatively regulate the cell cycle via phosphorylation of CDK1 and are considered potential drug targets. Herein, we investigated the structure-function relationship of human Wee1, Wee2 and Myt1 (PKMYT1). Purified recombinant full-length proteins and kinase domain constructs differed substantially in phosphorylation states and catalytic competency suggesting complex mechanisms of activation. A series of crystal structures revealed unique features that distinguish Wee1 and Wee2 from Myt1 and establish the structural basis of differential inhibition by the widely used Wee1 inhibitor MK-1775...
August 9, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28778089/identification-of-volasertib-resistant-mechanism-and-evaluation-of-combination-effects-with-volasertib-and-other-agents-on-acute-myeloid-leukemia
#18
Yoshiya Adachi, Yuichi Ishikawa, Hitoshi Kiyoi
Volasertib, a selective PLK1 inhibitor, was effective for acute myeloid leukemia (AML) patients in clinical trials. However, its efficacy was limited in mono-therapy, and a higher incidence of fatal events was revealed in the combination with low-dose cytarabine. Thus, optimization of combination therapy with volasertib and other agents is necessary for its clinical development, and the predictive factors for response or resistance to volasertib remain largely unknown. In this study, we investigated the resistance mechanism in volasertib-resistant cell lines and the combination effects with other agents, such as azacitidine (AZA), on AML cells...
July 26, 2017: Oncotarget
https://www.readbyqxmd.com/read/28767408/integration-of-genomic-transcriptomic-and-functional-profiles-of-aggressive-osteosarcomas-across-multiple-species
#19
Lara E Davis, Sophia Jeng, Matthew N Svalina, Elaine Huang, Janét Pittsenbarger, Emma L Cantor, Noah Berlow, Bernard Seguin, Atiya Mansoor, Shannon K McWeeney, Charles Keller
In complex, highly unstable genomes such as in osteosarcoma, targeting aberrant checkpoint processes (metabolic, cell cycle or immune) may prove more successful than targeting specific kinase or growth factor signaling pathways. Here, we establish a comparative oncology approach characterizing the most lethal osteosarcomas identified in a biorepository of tumors from three different species: human, mouse and canine. We describe the development of a genetically-engineered mouse model of osteosarcoma, establishment of primary cell cultures from fatal human tumors, and a biorepository of osteosarcoma surgical specimens from pet dogs...
July 25, 2017: Oncotarget
https://www.readbyqxmd.com/read/28726132/phase-i-dose-escalation-study-of-nms-1286937-an-orally-available-polo-like-kinase-1-inhibitor-in-patients-with-advanced-or-metastatic-solid-tumors
#20
Glen J Weiss, Gayle Jameson, Daniel D Von Hoff, Barbara Valsasina, Cristina Davite, Claudia Di Giulio, Francesco Fiorentini, Rachele Alzani, Patrizia Carpinelli, Alessandro Di Sanzo, Arturo Galvani, Antonella Isacchi, Ramesh K Ramanathan
Background Pharmacological inhibition of polo-like kinase 1 (PLK1) represents a new approach for the treatment of solid tumors. This study was aimed at determining the first cycle dose-limiting toxicities (DLTs) and related maximum tolerated dose (MTD) of NMS-1286937, a selective ATP-competitive PLK1-specific inhibitor. Secondary objectives included evaluation of its safety and pharmacokinetic (PK) profile in plasma, its antitumor activity, and its ability to modulate intracellular targets in biopsied tissue...
July 20, 2017: Investigational New Drugs
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