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https://www.readbyqxmd.com/read/29445034/the-skp1-cullin-f-box-e3-ligase-%C3%AE-trcp-and-cdk2-cooperate-to-control-stil-abundance-and-centriole-number
#1
Christian Arquint, Fabien Cubizolles, Agathe Morand, Alexander Schmidt, Erich A Nigg
Deregulation of centriole duplication has been implicated in cancer and primary microcephaly. Accordingly, it is important to understand how key centriole duplication factors are regulated. E3 ubiquitin ligases have been implicated in controlling the levels of several duplication factors, including PLK4, STIL and SAS-6, but the precise mechanisms ensuring centriole homeostasis remain to be fully understood. Here, we have combined proteomics approaches with the use of MLN4924, a generic inhibitor of SCF E3 ubiquitin ligases, to monitor changes in the cellular abundance of centriole duplication factors...
February 2018: Open Biology
https://www.readbyqxmd.com/read/29434041/polo-like-kinase-4-inhibition-produces-polyploidy-and-apoptotic-death-of-lung-cancers
#2
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/29361550/the-developing-drosophila-eye-an-oncoming-model-to-study-centriole-reduction
#3
Maria Giovanna Riparbelli, Veronica Persico, Marco Gottardo, Giuliano Callaini
In the developing Drosophila eye the centrioles of the differentiating retinal cells are not surrounded by the microtubule nucleating γ-tubulin suggesting that they are unable to organize functional microtubule organizing centers. Consistent with this idea Cnn and Spd-2, involved in γ-tubulin recruitment, and the scaffold protein Plp that plays a role in the organization of the pericentriolar material are lost in the third larval stage. However, the centrioles maintain their structural integrity and both the parents accumulate Asl and Ana1...
January 19, 2018: Journal of Cell Science
https://www.readbyqxmd.com/read/29352113/polo-like-kinase-4-mediates-epithelial-mesenchymal-transition-in-neuroblastoma-via-pi3k-akt-signaling-pathway
#4
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/29340047/inhibition-of-polo-like-kinase-4-plk4-a-new-therapeutic-option-for-rhabdoid-tumors-and-pediatric-medulloblastoma
#5
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/29330283/centriole-overduplication-is-the-predominant-mechanism-leading-to-centrosome-amplification-in-melanoma
#6
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
https://www.readbyqxmd.com/read/29259455/human-male-infertility-and-its-genetic-causes
#7
REVIEW
Toshinobu Miyamoto, Gaku Minase, Takeshi Shin, Hiroto Ueda, Hiroshi Okada, Kazuo Sengoku
Background: Infertility affects about 15% of couples who wish to have children and half of these cases are associated with male factors. Genetic causes of azoospermia include chromosomal abnormalities, Y chromosome microdeletions, and specific mutations/deletions of several Y chromosome genes. Many researchers have analyzed genes in the AZF region on the Y chromosome; however, in 2003 the SYCP3 gene on chromosome 12 (12q23) was identified as causing azoospermia by meiotic arrest through a point mutation...
April 2017: Reproductive Medicine and Biology
https://www.readbyqxmd.com/read/29171762/plk4-a-link-between-centriole-biogenesis-and-cancer
#8
Radhika Radha Maniswami, Seema Prashanth, Archana Venkataramana Karanth, Sindhu Koushik, Hemalatha Govindaraj, Ramesh Mullangi, Sriram Rajagopal, Sooriya Kumar Jegatheesan
Polo like kinase (PLK) is known to play a pivotal role in various cell cycle processes to perpetuate proper division and growth of the cells. Polo like kinase-4 (PLK4) is one such kinase that appears in low abundance and plays a well-characterized role in centriole duplication. PLK4 deregulation (i.e. both overexpression and depletion of PLK4), leads to altered mitotic fidelity and thereby triggers tumorigenesis. Hence, over the last few years PLK4 has emerged as a potential therapeutic target for the treatment of various advanced cancers...
November 24, 2017: Expert Opinion on Therapeutic Targets
https://www.readbyqxmd.com/read/28972102/plk4-and-aurora-a-cooperate-in-the-initiation-of-acentriolar-spindle-assembly-in-mammalian-oocytes
#9
Leah Bury, Paula A Coelho, Angela Simeone, Samantha Ferries, Claire E Eyers, Patrick A Eyers, Magdalena Zernicka-Goetz, David M Glover
Establishing the bipolar spindle in mammalian oocytes after their prolonged arrest is crucial for meiotic fidelity and subsequent development. In contrast to somatic cells, the first meiotic spindle assembles in the absence of centriole-containing centrosomes. Ran-GTP can promote microtubule nucleation near chromatin, but additional unidentified factors are postulated for the activity of multiple acentriolar microtubule organizing centers in the oocyte. We now demonstrate that partially overlapping, nonredundant functions of Aurora A and Plk4 kinases contribute to initiate acentriolar meiosis I spindle formation...
November 6, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/28832566/analysis-of-centrosome-and-dna-damage-response-in-plk4-associated-seckel-syndrome
#10
Tuba Dinçer, Gülden Yorgancıoğlu-Budak, Akgün Ölmez, İdris Er, Yavuz Dodurga, Özmert Ma Özdemir, Bayram Toraman, Adem Yıldırım, Nuran Sabir, Nurten A Akarsu, C Nur Semerci, Ersan Kalay
Microcephalic primordial dwarfism (MPD) is a group of autosomal recessive inherited single-gene disorders with intrauterine and postnatal global growth failure. Seckel syndrome is the most common form of the MPD. Ten genes are known with Seckel syndrome. Using genome-wide SNP genotyping and homozygosity mapping we mapped a Seckel syndrome gene to chromosomal region 4q28.1-q28.3 in a Turkish family. Direct sequencing of PLK4 (polo-like kinase 4) revealed a homozygous splicing acceptor site transition (c.31-3 A>G) that results in a premature translation termination (p...
October 2017: European Journal of Human Genetics: EJHG
https://www.readbyqxmd.com/read/28819179/identification-of-polo-like-kinases-as-potential-novel-drug-targets-for-influenza-a-virus
#11
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/28818446/characterization-of-a-highly-selective-inhibitor-of-the-aurora-kinases
#12
Fleur M Ferguson, Zainab M Doctor, Apirat Chaikuad, Taebo Sim, Nam Doo Kim, Stefan Knapp, Nathanael S Gray
Aurora kinases play an essential role in mitosis and cell cycle regulation. In recent years Aurora kinases have proved popular cancer targets and many inhibitors have been developed. The majority of these clinical candidates are multi-targeted, rendering them inappropriate as tools for studying Aurora kinase mediated signaling. Here we report discovery of a highly selective inhibitor of Aurora kinases A, B and C, with potent cellular activity and minimal off-target activity (PLK4). The X-ray co-crystal structure of Aurora A in complex with compound 2 is reported, and provides insights into the structural determinants of ligand binding and selectivity...
September 15, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28807782/modulating-protein-protein-interactions-of-the-mitotic-polo-like-kinases-to-target-mutant-kras
#13
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...
August 17, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28562169/plk4-phosphorylation-of-cp110-is-required-for-efficient-centriole-assembly
#14
Miseon Lee, Mi Young Seo, Jaerak Chang, Deog Su Hwang, Kunsoo Rhee
Centrioles are assembled during S phase and segregated into 2 daughter cells at the end of mitosis. The initiation of centriole assembly is regulated by polo-like kinase 4 (PLK4), the major serine/threonine kinase in centrioles. Despite its importance in centriole duplication, only a few substrates have been identified, and the detailed mechanism of PLK4 has not been fully elucidated. CP110 is a coiled-coil protein that plays roles in centriolar length control and ciliogenesis in mammals. Here, we revealed that PLK4 specifically phosphorylates CP110 at the S98 position...
June 18, 2017: Cell Cycle
https://www.readbyqxmd.com/read/28515047/centrosome-amplification-a-suspect-in-breast-cancer-and-racial-disparities
#15
Angela Ogden, Padmashree C G Rida, Ritu Aneja
The multifaceted involvement of centrosome amplification (CA) in tumorigenesis is coming into focus following years of meticulous experimentation, which have elucidated the powerful abilities of CA to promote cellular invasion, disrupt stem cell division, drive chromosomal instability (CIN), and perturb tissue architecture, activities that can accelerate tumor progression. Integration of the extant in vitro, in vivo, and clinical data suggests that in some tissues CA may be a tumor-initiating event, in others a consequential "hit" in multistep tumorigenesis, and in still others non-tumorigenic...
May 17, 2017: Endocrine-related Cancer
https://www.readbyqxmd.com/read/28474672/stat3-regulates-centrosome-clustering-in-cancer-cells-via-stathmin-plk1
#16
Edward J Morris, Eiko Kawamura, Jordan A Gillespie, Aruna Balgi, Nagarajan Kannan, William J Muller, Michel Roberge, Shoukat Dedhar
Cancer cells frequently have amplified centrosomes that must be clustered together to form a bipolar mitotic spindle, and targeting centrosome clustering is considered a promising therapeutic strategy. A high-content chemical screen for inhibitors of centrosome clustering identified Stattic, a Stat3 inhibitor. Stat3 depletion and inhibition in cancer cell lines and in tumours in vivo caused significant inhibition of centrosome clustering and viability. Here we describe a transcription-independent mechanism for Stat3-mediated centrosome clustering that involves Stathmin, a Stat3 interactor involved in microtubule depolymerization, and the mitotic kinase PLK1...
May 5, 2017: Nature Communications
https://www.readbyqxmd.com/read/28447620/dna-replication-licensing-factor-cdc6-and-plk4-kinase-antagonistically-regulate-centrosome-duplication-via-sas-6
#17
Xiaowei Xu, Shijiao Huang, Boyan Zhang, Fan Huang, Wangfei Chi, Jingyan Fu, Gang Wang, Si Li, Qing Jiang, Chuanmao Zhang
Centrosome number is tightly controlled during the cell cycle to ensure proper spindle assembly and cell division. However, the underlying mechanism that controls centrosome number remains largely unclear. We show herein that the DNA replication licensing factor Cdc6 is recruited to the proximal side of the centrioles via cyclin A to negatively regulate centrosome duplication by binding and inhibiting the cartwheel protein Sas-6 from forming a stable complex with another centriole duplication core protein, STIL...
April 27, 2017: Nature Communications
https://www.readbyqxmd.com/read/28401181/kat2-mediated-plk4-acetylation-contributes-to-genomic-stability-by-preserving-centrosome-number
#18
Marjorie Fournier, László Tora
We have recently identified the first human lysine (K) acetyltransferase 2A and 2B (called KAT2A/2B; known also as GCN5/PCAF, respectively)-dependent acetylome and revealed a mechanism by which KAT2A/2B-mediated acetylation of serine/threonine polo-like kinase 4 (PLK4) maintains correct centrosome number in human cells, therefore contributing to the maintenance of genome stability.(1).
2017: Molecular & Cellular Oncology
https://www.readbyqxmd.com/read/28398638/a-functional-screening-of-the-kinome-identifies-the-polo-like-kinase-4-as-a-potential-therapeutic-target-for-malignant-rhabdoid-tumors-and-possibly-other-embryonal-tumors-of-the-brain
#19
Simone Treiger Sredni, Mario Suzuki, Jian-Ping Yang, Jacek Topczewski, Anders W Bailey, Tufan Gokirmak, Jeffrey N Gross, Alexandre de Andrade, Akihide Kondo, David R Piper, Tadanori Tomita
PURPOSE: Malignant rhabdoid tumors (MRTs) are deadly embryonal tumors of the infancy. With poor survival and modest response to available therapies, more effective and less toxic treatments are needed. We hypothesized that a systematic screening of the kinome will reveal kinases that drive rhabdoid tumors and can be targeted by specific inhibitors. METHODS: We individually mutated 160 kinases in a well-characterized rhabdoid tumor cell line (MON) using lentiviral clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9)...
November 2017: Pediatric Blood & Cancer
https://www.readbyqxmd.com/read/28283778/plk1-associated-micrornas-are-correlated-with-pediatric-medulloblastoma-prognosis
#20
Julia Alejandra Pezuk, María Sol Brassesco, Ricardo Santos de Oliveira, Hélio Rubens Machado, Luciano Neder, Carlos Alberto Scrideli, Luiz Gonzaga Tone
PURPOSE: Medulloblastoma (MB) is the most common malignant tumor of the central nervous system (CNS) in children. Despite its relative good survival rates, treatment can cause long time sequels and may impair patients' lifespan and quality, making the search for new treatment options still necessary. Polo like kinases (PLKs) constitute a five-member serine/threonine kinases family (PLK 1-5) that regulates different stages during cell cycle. Abnormal PLKs expression has been observed in several cancer types, including MB...
April 2017: Child's Nervous System: ChNS: Official Journal of the International Society for Pediatric Neurosurgery
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