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Polo-like kinase

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https://www.readbyqxmd.com/read/28821799/plk1-bound-to-bub1-contributes-to-spindle-assembly-checkpoint-activity-during-mitosis
#1
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
#2
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
#3
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
#4
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/28816348/transition-metal-dependent-regulation-of-the-signal-transduction-cascade-driving-oocyte-meiosis
#5
Stephanie Schaefer-Ramadan, Satanay Hubrack, Khaled Machaca
The G2-M transition of the cell cycle requires the activation of members of the Cdc25 dual specificity phosphatase family. Using Xenopus oocyte maturation as a model system, we have previously shown that chelation of transition metals blocks meiosis progression by inhibiting Cdc25C activation. Here, using approaches that allow for the isolation of very pure and active recombinant Cdc25C, we show that Cdc25C does not bind zinc as previously reported. Additionally, we show that mutants in the disordered C-terminal end of Cdc25C are poor initiators of meiosis, likely due to their inability to localize to the proper sub-cellular location...
August 17, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/28807782/modulating-protein-protein-interactions-of-the-mitotic-polo-like-kinases-to-target-mutant-kras
#6
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/28803909/depletion-of-the-mitotic-kinase-cdc5p-in-candida-albicans-results-in-the-formation-of-elongated-buds-that-switch-to-the-hyphal-fate-over-time-in-a-ume6p-and-hgc1p-dependent-manner
#7
Amandeep Glory, Chloë Triplet van Oostende, Anja Geitmann, Catherine Bachewich
The fungal pathogen Candida albicans differentiates between yeast, hyphae and pseudohyphae in order to enhance survival in the human host. Environmental cues induce hyphal development and expression of hyphal-specific genes. Filaments also result from yeast cell cycle arrest, but the nature of these cells and their mechanisms of formation are less clear. We previously demonstrated that depletion of the mitotic polo-like kinase Cdc5p resulted in the production of filaments under yeast growth conditions that were distinct from hyphae with respect to several criteria, yet expressed hyphal-specific genes at later stages of development...
August 10, 2017: Fungal Genetics and Biology: FG & B
https://www.readbyqxmd.com/read/28792760/structural-basis-of-wee-kinases-functionality-and-inactivation-by-diverse-small-molecule-inhibitors
#8
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/28781233/phospho-h1-decorates-the-inter-chromatid-axis-and-is-evicted-along-with-shugoshin-by-set-during-mitosis
#9
Swathi Krishnan, Arne H Smits, Michiel Vermeulen, Danny Reinberg
Precise control of sister chromatid separation during mitosis is pivotal to maintaining genomic integrity. Yet, the regulatory mechanisms involved are not well understood. Remarkably, we discovered that linker histone H1 phosphorylated at S/T18 decorated the inter-chromatid axial DNA on mitotic chromosomes. Sister chromatid resolution during mitosis required the eviction of such H1S/T18ph by the chaperone SET, with this process being independent of and most likely downstream of arm-cohesin dissociation. SET also directed the disassembly of Shugoshins in a polo-like kinase 1-augmented manner, aiding centromere resolution...
August 17, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28770345/functions-and-regulation-of-the-polo-like-kinase-cdc5-in-the-absence-and-presence-of-dna-damage
#10
REVIEW
Vladimir V Botchkarev, James E Haber
Polo-like kinases are essential cell cycle regulators that are conserved from yeast to humans. Unlike higher eukaryotes, who express multiple Polo-like kinase family members that perform many important functions, budding yeast express only a single Polo-like kinase, Cdc5, which is the homolog of mammalian cell cycle master regulator Polo-like kinase 1. Cdc5 is a fascinating multifaceted protein that is programmed to target its many substrates in a timely, sequential manner to ensure proper cell cycle progression...
August 2, 2017: Current Genetics
https://www.readbyqxmd.com/read/28767408/integration-of-genomic-transcriptomic-and-functional-profiles-of-aggressive-osteosarcomas-across-multiple-species
#11
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/28766886/small-cell-lung-carcinoma-cell-line-screen-of-etoposide-carboplatin-plus-a-third-agent
#12
Beverly A Teicher, Thomas Silvers, Michael Selby, Rene Delosh, Julie Laudeman, Chad Ogle, Russell Reinhart, Ralph Parchment, Julia Krushkal, Dmitriy Sonkin, Larry Rubinstein, Joel Morris, David Evans
The SCLC combination screen examined a 9-point concentration response of 180 third agents, alone and in combination with etoposide/carboplatin. The predominant effect of adding a third agent to etoposide/carboplatin was additivity. Less than additive effects occurred frequently in SCLC lines sensitive to etoposide/carboplatin. In SCLC lines with little or no response to etoposide/carboplatin, greater than additive SCLC killing occurred over the entire spectrum of SCLC lines but never occurred in all SCLC lines...
August 2017: Cancer Medicine
https://www.readbyqxmd.com/read/28749534/polo-like-kinase-1-a-key-cellular-target-for-anti-hbv-therapy
#13
EDITORIAL
Michael M C Lai, Wen-Chi Su
No abstract text is available yet for this article.
July 27, 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
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
#14
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
https://www.readbyqxmd.com/read/28724602/the-clinical-and-prognostic-value-of-polo-like-kinase-1-in-lung-squamous-cell-carcinoma-patients-immunohistochemical-analysis
#15
Hefei Li, Haibo Wang, Zhenqing Sun, Qiang Guo, Hongyun Shi, Youchao Jia
Polo-like kinase 1 (PLK1) has been suggested to serve as oncogene in most human cancers. The aim of our study is to present more evidence about the clinical and prognostic value of PLK1 in lung squamous cell carcinoma patients. The status of PLK1 was observed in lung adenocarcinoma, lung squamous cell carcinoma and normal lung tissues through analyzing microarray data set (GEO accession number: GSE1213 and GSE 3627). PLK1 mRNA and protein expressions were detected in lung squamous cell carcinoma and normal lung tissues by using qRT-PCR and immunohistochemistry...
July 19, 2017: Bioscience Reports
https://www.readbyqxmd.com/read/28721210/current-progress-and-future-perspectives-in-the-development-of-anti-polo-like-kinase-1-therapeutic-agents
#16
REVIEW
Jung-Eun Park, David Hymel, Terrence R Burke, Kyung S Lee
Although significant levels of side effects are often associated with their use, microtubule-directed agents that primarily target fast-growing mitotic cells have been considered to be some of the most effective anti-cancer therapeutics. With the hope of developing new-generation anti-mitotic agents with reduced side effects and enhanced tumor specificity, researchers have targeted various proteins whose functions are critically required for mitotic progression. As one of the highly attractive mitotic targets, polo-like kinase 1 (Plk1) has been the subject of an extensive effort for anti-cancer drug discovery...
2017: F1000Research
https://www.readbyqxmd.com/read/28720575/hsp72-and-nek6-cooperate-to-cluster-amplified-centrosomes-in-cancer-cells
#17
Josephina Sampson, Laura O'Regan, Martin Js Dyer, Richard Bayliss, Andrew M Fry
Cancer cells frequently possess extra amplified centrosomes clustered into two poles whose pseudo-bipolar spindles exhibit reduced fidelity of chromosome segregation and promote genetic instability. Inhibition of centrosome clustering triggers multipolar spindle formation and mitotic catastrophe, offering an attractive therapeutic approach to selectively kill cells with amplified centrosomes. However, mechanisms of centrosome clustering remain poorly understood. Here, we identify a new pathway that acts through NIMA-related kinase 6 (Nek6) and Hsp72 to promote centrosome clustering...
July 18, 2017: Cancer Research
https://www.readbyqxmd.com/read/28708135/regulation-of-plk1-through-competition-between-hnrnpk-mir-149-3p-and-mir-193b-5p
#18
Chang Hoon Shin, Hong Lee, Hye Ree Kim, Kyung Hee Choi, Je-Gun Joung, Hyeon Ho Kim
Polo-like kinase 1 (PLK1) is a critical regulator of cell cycle progression and apoptosis. However, its regulation remains poorly understood. In the present study, we investigated the molecular mechanism underlying the post-transcriptional regulation of PLK1. We observed that heterogeneous nuclear ribonucleoprotein K (hnRNPK) and PLK1 were positively associated in several different cancers and high expression levels of them correlated with poor prognosis in patients with cancer. Knockdown of hnRNPK resulted in reduced expression of PLK1, whereas conversely, PLK1 expression was increased in hnRNPK-overexpressing cells...
July 14, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/28694245/fundamental-cell-cycle-kinases-collaborate-to-ensure-timely-destruction-of-the-synaptonemal-complex-during-meiosis
#19
Bilge Argunhan, Wing-Kit Leung, Negar Afshar, Yaroslav Terentyev, Vijayalakshmi V Subramanian, Yasuto Murayama, Andreas Hochwagen, Hiroshi Iwasaki, Tomomi Tsubouchi, Hideo Tsubouchi
The synaptonemal complex (SC) is a proteinaceous macromolecular assembly that forms during meiotic prophase I and mediates adhesion of paired homologous chromosomes along their entire lengths. Although prompt disassembly of the SC during exit from prophase I is a landmark event of meiosis, the underlying mechanism regulating SC destruction has remained elusive. Here, we show that DDK (Dbf4-dependent Cdc7 kinase) is central to SC destruction. Upon exit from prophase I, Dbf4, the regulatory subunit of DDK, directly associates with and is phosphorylated by the Polo-like kinase Cdc5...
July 10, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28692064/plk1-regulates-contraction-of-postmitotic-smooth-muscle-cells-and-is-required-for-vascular-homeostasis
#20
Guillermo de Cárcer, Paulina Wachowicz, Sara Martínez-Martínez, Jorge Oller, Nerea Méndez-Barbero, Beatriz Escobar, Alejandra González-Loyola, Tohru Takaki, Aicha El Bakkali, Juan A Cámara, Luis J Jiménez-Borreguero, Xosé R Bustelo, Marta Cañamero, Francisca Mulero, María de Los Ángeles Sevilla, María Jose Montero, Juan Miguel Redondo, Marcos Malumbres
Polo-like kinase 1 (PLK1), an essential regulator of cell division, is currently undergoing clinical evaluation as a target for cancer therapy. We report an unexpected function of Plk1 in sustaining cardiovascular homeostasis. Plk1 haploinsufficiency in mice did not induce obvious cell proliferation defects but did result in arterial structural alterations, which frequently led to aortic rupture and death. Specific ablation of Plk1 in vascular smooth muscle cells (VSMCs) led to reduced arterial elasticity, hypotension, and an impaired arterial response to angiotensin II in vivo...
August 2017: Nature Medicine
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