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Polo-like kinase

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https://www.readbyqxmd.com/read/28102733/plk1-polo-like-kinase-1-inhibits-mtor-complex-1-and-promotes-autophagy
#1
Stefanie Ruf, Alexander Martin Heberle, Miriam Langelaar-Makkinje, Sara Gelino, Deepti Wilkinson, Carolin Gerbeth, Jennifer Jasmin Schwarz, Birgit Holzwarth, Bettina Warscheid, Chris Meisinger, Marcel A T M van Vugt, Ralf Baumeister, Malene Hansen, Kathrin Thedieck
Mechanistic target of rapamycin complex 1 (MTORC1) and PLK1 (polo like kinase 1) are major drivers of cancer cell growth and proliferation, and inhibitors of both protein kinases are currently being investigated in clinical studies. To date, MTORC1's and PLK1's functions are mostly studied separately, and reports on their mutual crosstalk are scarce. Here, we identify PLK1 as a physical MTORC1 interactor in human cancer cells. PLK1 inhibition enhances MTORC1 activity under nutrient sufficiency and in starved cells, and PLK1 directly phosphorylates the MTORC1 component RPTOR/RAPTOR in vitro...
January 19, 2017: Autophagy
https://www.readbyqxmd.com/read/28074435/plk1-inhibition-leads-to-a-failure-of-mitotic-division-during-the-first-mitotic-division-in-pig-embryos
#2
Zixiao Zhang, Changchao Chen, Panpan Cui, Yaya Liao, Lingyun Yao, Yue Zhang, Rong Rui, Shiqiang Ju
PURPOSE: This study was conducted to examine the dynamic distribution of polo-like 1 kinase (Plk1) and the possible role it plays in first mitotic division during early porcine embryo development. METHODS: Indirect immunofluorescence and confocal microscopy imaging techniques combined with western blot analyses were used to study the dynamic expression and subcellular localization of Plk1 protein in pig parthenogenetic embryos. Finally, a selective Plk1 inhibitor, GSK461364, was used to evaluate the potential role of Plk1 during this special stage...
January 10, 2017: Journal of Assisted Reproduction and Genetics
https://www.readbyqxmd.com/read/28069876/targeting-plk1-to-enhance-efficacy-of-olaparib-in-castration-resistant-prostate-cancer
#3
Xiaoqi Liu, Jie Li, Ruixin Wang, Yifan Kong, Meaghan M Broman, Colin Carlock, Long Chen, Zhiguo Li, Elia Farah, Timothy L Ratliff
Olaparib is a FDA-approved PARP inhibitor (PARPi) that has shown promise as a synthetic lethal treatment approach for BRCA-mutant castration-resistant prostate cancer (CRPC) in clinical use. However, emerging data has also shown that even BRCA-mutant cells may be resistant to PARPi. The mechanistic basis for these drug resistances is poorly understood. Polo-like kinase 1 (Plk1), a critical regulator of many cell cycle events, is significantly elevated upon castration of mice carrying xenograft prostate tumors...
January 9, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28069132/molecular-regulation-of-the-spindle-assembly-checkpoint-by-kinases-and-phosphatases
#4
G Manic, F Corradi, A Sistigu, S Siteni, I Vitale
The spindle assembly checkpoint (SAC) is a surveillance mechanism contributing to the preservation of genomic stability by monitoring the microtubule attachment to, and/or the tension status of, each kinetochore during mitosis. The SAC halts metaphase to anaphase transition in the presence of unattached and/or untensed kinetochore(s) by releasing the mitotic checkpoint complex (MCC) from these improperly-oriented kinetochores to inhibit the anaphase-promoting complex/cyclosome (APC/C). The reversible phosphorylation of a variety of substrates at the kinetochore by antagonistic kinases and phosphatases is one major signaling mechanism for promptly turning on or turning off the SAC...
2017: International Review of Cell and Molecular Biology
https://www.readbyqxmd.com/read/28061448/targeting-basal-like-breast-tumors-with-bromodomain-and-extraterminal-domain-bet-and-polo-like-kinase-inhibitors
#5
Cristina Nieto-Jiménez, Ana Alcaraz-Sanabria, Javier Pérez-Peña, Verónica Corrales-Sánchez, Gemma Serrano-Heras, Eva M Galán-Moya, Leticia Serrano-Oviedo, Juan Carlos Montero, Miguel Burgos, Juan Llopis, Atanasio Pandiella, Alberto Ocaña
Metastatic triple negative breast cancer (TNBC) is an incurable disease with limited therapeutic options, and no targeted therapies available. Triple negative tumors and the basal-like genomic subtype, are both characterized by a high proliferation rate and an increase in cell division. In this context, protein kinases involved in the mitotic formation have a relevant role in this tumor subtype. Recently, Bromodomain and extraterminal domain (BET) inhibitors have shown to be active in this disease by modulating the expression of several transcription factors...
January 3, 2017: Oncotarget
https://www.readbyqxmd.com/read/28052114/crl4wdr1-controls-polo-like-kinase-protein-abundance-to-promote-bilobe-duplication-basal-body-segregation-and-flagellum-attachment-in-trypanosoma-brucei
#6
Huiqing Hu, Qing Zhou, Xianxian Han, Ziyin Li
The Polo-like kinase homolog in Trypanosoma brucei, TbPLK, plays essential roles in basal body segregation, flagellum attachment and cytokinesis. The level of TbPLK protein is tightly controlled, but the underlying mechanism remains elusive. Here, we report a Cullin-RING ubiquitin ligase composed of Cullin4, the DNA damage-binding protein 1 homolog TbDDB1 and a WD40-repeat protein WDR1 that controls TbPLK abundance in the basal body and the bilobe. WDR1, through its C-terminal domain, interacts with the PEST motif in TbPLK and, through its N-terminal WD40 motif, binds to TbDDB1...
January 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28036269/the-gsk461364-plk1-inhibitor-exhibits-strong-antitumoral-activity-in-preclinical-neuroblastoma-models
#7
Kristian W Pajtler, Natalie Sadowski, Sandra Ackermann, Kristina Althoff, Kerstin Schönbeck, Katharina Batzke, Simon Schäfers, Andrea Odersky, Lukas Heukamp, Kathy Astrahantseff, Annette Künkele, Hedwig E Deubzer, Alexander Schramm, Annika Sprüssel, Theresa Thor, Sven Lindner, Angelika Eggert, Matthias Fischer, Johannes H Schulte
Polo-like kinase 1 (PLK1) is a serine/threonine kinase that promotes G2/M-phase transition, is expressed in elevated levels in high-risk neuroblastomas and correlates with unfavorable patient outcome. Recently, we and others have presented PLK1 as a potential drug target for neuroblastoma, and reported that the BI2536 PLK1 inhibitor showed antitumoral actvity in preclinical neuroblastoma models. Here we analyzed the effects of GSK461364, a competitive inhibitor for ATP binding to PLK1, on typical tumorigenic properties of preclinical in vitro and in vivo neuroblastoma models...
December 27, 2016: Oncotarget
https://www.readbyqxmd.com/read/28030843/targeted-delivery-of-crispr-cas9-to-prostate-cancer-by-modified-grna-using-a-flexible-aptamer-cationic-liposome
#8
Shuai Zhen, Y Takahashi, S Narita, Yi-Chen Yang, Xu Li
The potent ability of CRISPR/Cas9 system to inhibit the expression of targeted gene is being exploited as a new class of therapeutics for a variety of diseases. However, the efficient and safe delivery of CRISPR/Cas9 into specific cell populations is still the principal challenge in the clinical development of CRISPR/Cas9 therapeutics. In this study, a flexible aptamer-liposome-CRISPR/Cas9 chimera was designed to combine efficient delivery and increased flexibility. Our chimera incorporated an RNA aptamer that specifically binds prostate cancer cells expressing the prostate-specific membrane antigen as a ligand...
December 21, 2016: Oncotarget
https://www.readbyqxmd.com/read/27992122/phosphatase-stable-phosphoamino-acid-mimetics-that-enhance-binding-affinities-with-the-polo-box-domain-of-polo-like-kinase-1
#9
David Hymel, Terrence Burke
(2S,3R)-2-Amino-3-methyl-4-phosphono-butanoic acid (Pmab) is a phosphatase-stable analog of phosphothreonine (pThr), which has been used in a variety of biological contexts. These include peptidomimetic ligands that bind to the polo-box domain (PBD) of polo-like kinase 1 (Plk1) with affinities approaching that of the corresponding pThr-containing peptides. However, Pmab is not widely used, because there are no direct, high-yield preparations of suitably protected reagents. We have now achieved an efficient synthesis of protected Pmab, as well as variants with different substituents at the 3R-center...
December 19, 2016: ChemMedChem
https://www.readbyqxmd.com/read/27979967/daz-interacting-protein-1-dzip1-phosphorylation-by-polo-like-kinase-1-plk1-regulates-the-centriolar-satellites-localization-of-the-bbsome-during-the-cell-cycle
#10
Boyan Zhang, Gang Wang, Xiaowei Xu, Sisi Yang, Tenghan Zhuang, Guopeng Wang, He Ren, Steven Y Cheng, Qing Jiang, Chuanmao Zhang
The function of the primary cilia, which is assembled in most vertebrate cells, is achieved by transport in and out of kinds of signaling receptors. The BBSome protein complex could recognize and target membrane proteins to the cilia, but how the BBSome itself is transported into the cilia is poorly understood. Here we demonstrate that the centrosome protein Dzip1 mediates the assembly of the BBSome-Dzip1-PCM1 complex in the centriolar satellites (CS) at the G0 phase for ciliary translocation of the BBSome...
December 15, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27965913/blood-plasma-of-patients-with-parkinson-s-disease-increases-alpha-synuclein-aggregation-and-neurotoxicity
#11
Peng Wang, Xin Li, Xuran Li, Weiwei Yang, Shun Yu
A pathological hallmark of Parkinson's disease (PD) is formation of Lewy bodies in neurons of the brain. This has been attributed to the spread of α-synuclein (α-syn) aggregates, which involves release of α-syn from a neuron and its reuptake by a neighboring neuron. We found that treatment with plasma from PD patients induced more α-syn phosphorylation and oligomerization than plasma from normal subjects (NS). Compared with NS plasma, PD plasma added to primary neuron cultures caused more cell death in the presence of extracellular α-syn...
2016: Parkinson's Disease
https://www.readbyqxmd.com/read/27965426/mitotic-phosphotyrosine-network-analysis-reveals-that-tyrosine-phosphorylation-regulates-polo-like-kinase-1-plk1
#12
Danielle Caron, Dominic P Byrne, Philippe Thebault, Denis Soulet, Christian R Landry, Patrick A Eyers, Sabine Elowe
Tyrosine phosphorylation is closely associated with cell proliferation. During the cell cycle, serine and threonine phosphorylation plays the leading role, and such phosphorylation events are most dynamic during the mitotic phase of the cell cycle. However, mitotic phosphotyrosine is not well characterized. Although a few functionally-relevant mitotic phosphotyrosine sites have been characterized, evidence suggests that this modification may be more prevalent than previously appreciated. Here, we examined tyrosine phosphorylation in mitotic human cells including those on spindle-associated proteins...
December 13, 2016: Science Signaling
https://www.readbyqxmd.com/read/27935233/kinetic-analysis-of-de-novo-centriole-assembly-in-heat-shocked-mammalian-cells
#13
In Keol Baek, Yeun Kyu Jang, Tae H Lee, JooHun Lee
Mammalian cells are capable of de novo centriole formation after the removal of existing centrioles. This suggests that de novo centriole assembly is repressed in normally duplicating cells to maintain a constant number of centrioles in the cells. However, neither the mechanism of de novo centriole assembly nor that of its hypothesized repression is understood due to the lack of an experimental system. We found that the heat shock (HS; 42°C, 2 h) of mouse embryonic fibroblasts caused the separation of centriole pairs, a transient increase in polo-like kinase (Plk) 4 expression, and the formation of a complex containing γ-tubulin, pericentrin, HS protein (Hsp) 90, and Plk4, in approximately half of the cells...
December 9, 2016: Cytoskeleton
https://www.readbyqxmd.com/read/27924005/sub1-contacts-the-rna-polymerase-ii-stalk-to-modulate-mrna-synthesis
#14
Miguel Garavís, Noelia González-Polo, Paula Allepuz-Fuster, Jaime Alegrio Louro, Carlos Fernández-Tornero, Olga Calvo
Biogenesis of messenger RNA is critically influenced by the phosphorylation state of the carboxy-terminal domain (CTD) in the largest RNA polymerase II (RNAPII) subunit. Several kinases and phosphatases are required to maintain proper CTD phosphorylation levels and, additionally, several other proteins modulate them, including Rpb4/7 and Sub1. The Rpb4/7 heterodimer, constituting the RNAPII stalk, promote phosphatase functions and Sub1 globally influences CTD phosphorylation, though its mechanism remains mostly unknown...
December 6, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27922680/identification-of-key-genes-induced-by-platelet-rich-plasma-in-human-dermal-papilla-cells-using-bioinformatics-methods
#15
Haiyan Shen, Hanxiao Cheng, Haihua Chen, Jufang Zhang
Dermal papilla cells (DPCs) are located at the base of hair follicles, and are known to induce hair follicle regeneration. Platelet-rich plasma (PRP) functions in hair follicle regeneration. To investigate the influence of PRP on DPCs, the present study analyzed RNA‑seq data of human hair dermal papilla cells (HHDPCs) that were treated or untreated by PRP. The data included in the RNA‑seq were from two normal and two treated HHDPC samples. Following identification by Cuffdiff software, differentially expressed genes (DEGs) underwent enrichment analyses, and protein-protein interaction networks were constructed using Cytoscape software...
January 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/27911707/the-plk4-stil-sas-6-module-at-the-core-of-centriole-duplication
#16
REVIEW
Christian Arquint, Erich A Nigg
Centrioles are microtubule-based core components of centrosomes and cilia. They are duplicated exactly once during S-phase progression. Central to formation of each new (daughter) centriole is the formation of a nine-fold symmetrical cartwheel structure onto which microtubule triplets are deposited. In recent years, a module comprising the protein kinase polo-like kinase 4 (PLK4) and the two proteins STIL and SAS-6 have been shown to stay at the core of centriole duplication. Depletion of any one of these three proteins blocks centriole duplication and, conversely, overexpression causes centriole amplification...
October 15, 2016: Biochemical Society Transactions
https://www.readbyqxmd.com/read/27908889/microrna-146a-induces-lineage-negative-bone-marrow-cell-apoptosis-and-senescence-by-targeting-polo-like-kinase-2-expression
#17
Shanming Deng, Huilan Wang, Chunling Jia, Shoukang Zhu, Xianming Chu, Qi Ma, Jianqin Wei, Emily Chen, Wei Zhu, Conrad J Macon, Dushyantha T Jayaweera, Derek M Dykxhoorn, Chunming Dong
OBJECTIVE: Lineage-negative bone marrow cells (lin- BMCs) are enriched in endothelial progenitor cells and mediate vascular repair. Aging-associated senescence and apoptosis result in reduced number and functionality of lin- BMCs, impairing their prorepair capacity. The molecular mechanisms underlying lin- BMC senescence and apoptosis are poorly understood. MicroRNAs (miRNAs) regulate many important biological processes. The identification of miRNA-mRNA networks that modulate the health and functionality of lin- BMCs is a critical step in understanding the process of vascular repair...
December 1, 2016: Arteriosclerosis, Thrombosis, and Vascular Biology
https://www.readbyqxmd.com/read/27906199/microduplication-of-the-arid1a-gene-causes-intellectual-disability-with-recognizable-syndromic-features
#18
Marie Bidart, Michèle El Atifi, Sarra Miladi, John Rendu, Véronique Satre, Pierre F Ray, Caroline Bosson, Françoise Devillard, Daphné Lehalle, Valérie Malan, Jeanne Amiel, Maria Antonietta Mencarelli, Margherita Baldassarri, Alessandra Renieri, Jill Clayton-Smith, Gaëlle Vieville, Julien Thevenon, Florence Amblard, François Berger, Pierre-Simon Jouk, Charles Coutton
PURPOSE: To determine whether duplication of the ARID1A gene is responsible for a new recognizable syndrome. METHODS: We describe four patients with a 1p36.11 microduplication involving ARID1A as identified by array-comparative genomic hybridization . We performed comparative transcriptomic analysis of patient-derived fibroblasts using RNA sequencing and evaluated the impact of ARID1A duplication on the cell cycle using fluorescence-activated cell sorting. Functional relationships between differentially expressed genes were investigated with ingenuity pathway analysis (IPA)...
December 1, 2016: Genetics in Medicine: Official Journal of the American College of Medical Genetics
https://www.readbyqxmd.com/read/27904765/volasertib-suppresses-the-growth-of-human-hepatocellular-carcinoma-in-vitro-and-in-vivo
#19
Di-Wei Zheng, You-Qiu Xue, Yong Li, Jin-Ming Di, Jian-Ge Qiu, Wen-Ji Zhang, Qi-Wei Jiang, Yang Yang, Yao Chen, Meng-Ning Wei, Jia-Rong Huang, Kun Wang, Xing Wei, Zhi Shi
Hepatocellular carcinoma (HCC) is the sixth most frequent malignant tumor with poor prognosis, and its clinical therapeutic outcome is poor. Volasertib, a potent small molecular inhibitor of polo-like kinase 1 (PLK1), is currently tested for treatment of multiple cancers in the clinical trials. However, the antitumor effect of volasertib on HCC is still unknown. In this study, our data show that volasertib is able to induce cell growth inhibition, cell cycle arrest at G2/M phase and apoptosis with the spindle abnormalities in human HCC cells...
2016: American Journal of Cancer Research
https://www.readbyqxmd.com/read/27902970/activity-of-the-novel-polo-like-kinase-4-inhibitor-cfi-400945-in-pancreatic-cancer-patient-derived-xenografts
#20
I Lohse, J M Mason, P J Cao, Melania Pintilie, M R Bray, D W Hedley
BACKGROUND: Polo-like kinase 4 (PKL4) plays a key role in centriole replication. Hence PLK4 inhibition disrupts mitosis, and offers a novel approach to treating chromosomally unstable cancers, including pancreatic cancer. CFI-400945 is a first in class small molecule PLK4 inhibitor, currently undergoing early phase clinical trials. RESULTS: Treatment with CFI-400945 significantly reduced tumor growth and increased survival in four out of the six models tested. Consistent with PLK4 inhibition, we observed reduced expression of the proliferation marker Ki-67 associated with an increase in nuclear diameter during treatment with CFI-400945...
November 25, 2016: Oncotarget
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