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https://www.readbyqxmd.com/read/29521213/advances-in-spirocyclic-hybrids-chemistry-and-medicinal-actions
#1
Mohammed Benadallah, Oualid Talhi, Fatiha Nouali, Nourredine Choukchou-Braham, Khaldoun Bachari, Artur M S Silva
The present review deals with the progress in medicinal chemistry of spirocyclic compounds, a wider class of natural and synthetic organic molecules, defined as a hybrid of two molecular entities covalently linked via a unique tetrahedral carbon. This spiro central carbon confers to the molecules a tridimensional structurally oriented framework, which is found in many medicinally relevant compounds, a well-known example is the anti-hypertensive spironolactone. Various bioactive natural products possess the privileged spiro linkage and different chemo-types thereof become synthetically accessible since the 20th century...
March 9, 2018: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/29519803/fast-and-furious-or-not-plk4-dictates-the-pace
#2
Simon Gemble, Renata Basto
In each duplication cycle, daughter centrioles grow to the same length as their mothers. Which mechanisms regulate this fidelity to maintain centriole length is not known. In this issue, Aydogan et al. (2018. J. Cell Biol. https://doi.org/10.1083/jcb.201801014) report a novel role for Polo-like kinase 4 (Plk4). They found that Plk4 functions in a homeostatic manner to balance growth rate and growth period to set the final centriole size.
March 8, 2018: Journal of Cell Biology
https://www.readbyqxmd.com/read/29500190/a-homeostatic-clock-sets-daughter-centriole-size-in-flies
#3
Mustafa G Aydogan, Alan Wainman, Saroj Saurya, Thomas L Steinacker, Anna Caballe, Zsofia A Novak, Janina Baumbach, Nadine Muschalik, Jordan W Raff
Centrioles are highly structured organelles whose size is remarkably consistent within any given cell type. New centrioles are born when Polo-like kinase 4 (Plk4) recruits Ana2/STIL and Sas-6 to the side of an existing "mother" centriole. These two proteins then assemble into a cartwheel, which grows outwards to form the structural core of a new daughter. Here, we show that in early Drosophila melanogaster embryos, daughter centrioles grow at a linear rate during early S-phase and abruptly stop growing when they reach their correct size in mid- to late S-phase...
March 2, 2018: Journal of Cell Biology
https://www.readbyqxmd.com/read/29496738/an-ordered-pattern-of-ana2-phosphorylation-by-plk4-is-required-for-centriole-assembly
#4
Tiffany A McLamarrah, Daniel W Buster, Brian J Galletta, Cody J Boese, John M Ryniawec, Natalie Ann Hollingsworth, Amy E Byrnes, Christopher W Brownlee, Kevin C Slep, Nasser M Rusan, Gregory C Rogers
Polo-like kinase 4 (Plk4) initiates an early step in centriole assembly by phosphorylating Ana2/STIL, a structural component of the procentriole. Here, we show that Plk4 binding to the central coiled-coil (CC) of Ana2 is a conserved event involving Polo-box 3 and a previously unidentified putative CC located adjacent to the kinase domain. Ana2 is then phosphorylated along its length. Previous studies showed that Plk4 phosphorylates the C-terminal STil/ANa2 (STAN) domain of Ana2/STIL, triggering binding and recruitment of the cartwheel protein Sas6 to the procentriole assembly site...
March 1, 2018: Journal of Cell Biology
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
#5
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
#6
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 20, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29361550/the-developing-drosophila-eye-a-new-model-to-study-centriole-reduction
#7
Maria G 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, which are involved in γ-tubulin recruitment, and the scaffold protein Plp, which plays a role in the organization of the pericentriolar material, are lost in the third-instar larval stage. However, the centrioles maintain their structural integrity, and both the parent centrioles accumulate Asl and Ana1...
February 22, 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
#8
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
#9
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
#10
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...
March 2018: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29259455/human-male-infertility-and-its-genetic-causes
#11
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
#12
REVIEW
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...
January 2018: 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
#13
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
#14
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
#15
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
#16
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
#17
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
#18
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
#19
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
#20
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
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