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Georg Wandrey, Joel Wurzel, Kyra Hoffmann, Tobias Ladner, Jochen Büchs, Lorenz Meinel, Tessa Lühmann
BACKGROUND: Genetic code expansion has developed into an elegant tool to incorporate unnatural amino acids (uAA) at predefined sites in the protein backbone in response to an amber codon. However, recombinant production and yield of uAA comprising proteins are challenged due to the additional translation machinery required for uAA incorporation. RESULTS: We developed a microtiter plate-based high-throughput monitoring system (HTMS) to study and optimize uAA integration in the model protein enhanced green fluorescence protein (eGFP)...
2016: Journal of Biological Engineering
Tyler S Machovina, Rana Mainpal, Anahita Daryabeigi, Olivia McGovern, Dimitra Paouneskou, Sara Labella, Monique Zetka, Verena Jantsch, Judith L Yanowitz
Crossover (CO) recombination creates a physical connection between homologs that promotes their proper segregation at meiosis I (MI). Failure to realize an obligate CO causes homologs to attach independently to the MI spindle and separate randomly, leading to nondisjunction. However, mechanisms that determine whether homolog pairs have received crossovers remain mysterious. Here we describe a surveillance system in C. elegans that monitors recombination intermediates and couples their formation to meiotic progression...
October 1, 2016: Current Biology: CB
Yuma Nonomiya, Kohji Noguchi, Noritaka Tanaka, Takahiro Kasagaki, Kazuhiro Katayama, Yoshikazu Sugimoto
Polo-like kinase (PLK) is a cell-cycle regulator that is overexpressed in several cancer cell types. PLK is considered a novel target for cancer therapies, and several PLK inhibitors (PLKis), including BI 2536, BI 6727, and GSK461364, have been developed. In this study, we established five BI 2536-resistant cell lines from human colorectal cancer HCT 116 cells, to explore the resistance mechanism and identify predictable biomarkers of PLKis. We demonstrated that PLKi-induced caspase-8 activation was attenuated in the BI 2536-resistant cell lines...
October 3, 2016: Cancer Science
Ritam Chatterjee, Sukalpa Chattopadhyay, Sujata Law
Aplastic anemia, the paradigm of bone marrow failure, is characterized by pancytopenic peripheral blood and hypoplastic bone marrow. Among various etiologies, inappropriate use of DNA alkylating drugs like cyclophosphamide and busulfan often causes the manifestation of the dreadful disease. Cell cycle impairment in marrow hematopoietic stem/progenitor compartment together with cellular apoptosis has been recognized as culpable factors behind aplastic pathophysiologies. However, the intricate molecular mechanisms remain unrevealed till date...
November 2016: Molecular and Cellular Biochemistry
David Mahato, Dipayan Samanta, Sudit S Mukhopadhyay, R Navanietha Krishnaraj
Fanconi anemia (FA) is an autosomal recessive disorder with a high risk of malignancies including acute myeloid leukemia and squamous cell carcinoma. There is a constant search out of new potential therapeutic molecule to combat this disorder. In most cases, patients with FA develop haematological malignancies with acute myeloid leukemia and acute lymphoblastic leukemia. Identifying drugs which can efficiently block the pathways of both these disorders can be an ideal and novel strategy to treat FA. The curcumin, a natural compound obtained from turmeric is an interesting therapeutic molecule as it has been reported in the literature to combat both FA as well as leukemia...
September 8, 2016: Journal of Receptor and Signal Transduction Research
Taikangxiang Yun, Tan Qin, Ying Liu, Luhua Lai
Thiourea derivatives have drawn much attention for their latent capacities of biological activities. In this study, we designed acylthiourea compounds as polo-like kinase 1 (Plk1) polo-box domain (PBD) inhibitors. A series of acylthiourea derivatives without pan assay interference structure (PAINS) were synthesized. Four compounds with halogen substituents exhibited binding affinities to Plk1 PBD in low micromole range. The most potent compound (3v) showed selectivity over other subtypes of Plk PBDs and inhibited the kinase activity of full-length Plk1...
August 22, 2016: European Journal of Medicinal Chemistry
Oliver Wueseke, David Zwicker, Anne Schwager, Yao Liang Wong, Karen Oegema, Frank Jülicher, Anthony A Hyman, Jeffrey B Woodruff
Centrosomes are major microtubule-organizing centers composed of centrioles surrounded by an extensive proteinacious layer called the pericentriolar material (PCM). In Caenorhabditis elegans embryos, the mitotic PCM expands by Polo-like kinase 1 (PLK-1) phosphorylation-accelerated assembly of SPD-5 molecules into supramolecular scaffolds. However, how PLK-1 phosphorylation regulates SPD-5 assembly is not known. We found that a mutant version of SPD-5 that is insensitive to PLK-1 phosphorylation (SPD-5(4A)) could localize to PCM but was unable to rescue the reduction in PCM size and density when wild-type SPD-5 levels were decreased...
October 15, 2016: Biology Open
Irena Zurnic, Sylvia Hütter, Ute Rzeha, Nicole Stanke, Juliane Reh, Erik Müllers, Martin V Hamann, Tobias Kern, Gesche K Gerresheim, Fabian Lindel, Erik Serrao, Paul Lesbats, Alan N Engelman, Peter Cherepanov, Dirk Lindemann
Unlike for other retroviruses, only a few host cell factors that aid the replication of foamy viruses (FVs) via interaction with viral structural components are known. Using a yeast-two-hybrid (Y2H) screen with prototype FV (PFV) Gag protein as bait we identified human polo-like kinase 2 (hPLK2), a member of cell cycle regulatory kinases, as a new interactor of PFV capsids. Further Y2H studies confirmed interaction of PFV Gag with several PLKs of both human and rat origin. A consensus Ser-Thr/Ser-Pro (S-T/S-P) motif in Gag, which is conserved among primate FVs and phosphorylated in PFV virions, was essential for recognition by PLKs...
August 2016: PLoS Pathogens
Chetan C Rawal, Sara Riccardo, Chiara Pesenti, Matteo Ferrari, Federica Marini, Achille Pellicioli
Polo-like kinases (PLKs) control several aspects of eukaryotic cell division and DNA damage response. Remarkably, PLKs are overexpressed in several types of cancer, being therefore a marker of bad prognosis. As such, specific PLK kinase activity inhibitors are already used in clinical trial and the regulation of PLK activation is a relevant topic of cancer research. Phosphorylation of threonine residues in the T-loop of the kinase domain is pivotal for PLKs activation. Here, we show that T238A substitution in the T-loop reduces the kinase activity of Cdc5, the only PLK in Saccharomyces cerevisiae, with minor effect on cell growth in unperturbed conditions...
August 26, 2016: Cell Cycle
Nicola J Rutherford, Mieu Brooks, Benoit I Giasson
Pathological inclusions containing aggregated, highly phosphorylated (at serine129) α-synuclein (αS pSer129) are characteristic of a group of neurodegenerative diseases termed synucleinopathies. Antibodies to the pSer129 epitope can be highly sensitive in detecting αS inclusions in human tissue and experimental models of synucleinopathies. However, the generation of extensively specific pSer129 antibodies has been problematic, in some cases leading to the misinterpretation of αS inclusion pathology. One common issue is cross-reactivity to the low molecular mass neurofilament subunit (NFL) phosphorylated at Ser473...
2016: Acta Neuropathologica Communications
Norlaily Mohd Ali, M Nadeem Akhtar, Huynh Ky, Kian Lam Lim, Nadiah Abu, Seema Zareen, Wan Yong Ho, Han Kiat Alan-Ong, Sheau Wei Tan, Noorjahan Banu Alitheen, Jamil Bin Ismail, Swee Keong Yeap, Tunku Kamarul
Known as naturally occurring biologically active compounds, flavokawain A and B are the leading chalcones that possess anticancer properties. Another flavokawain derivative, (E)-1-(2'-Hydroxy-4',6'-dimethoxyphenyl)-3-(4-methylthio)phenyl)prop-2-ene-1-one (FLS) was characterized with (1)H-nuclear magnetic resonance, electron-impact mas spectrometry, infrared spectroscopy, and ultraviolet ((1)H NMR, EI-MS, IR, and UV) spectroscopic techniques. FLS cytotoxic efficacy against human cancer cells (MCF-7, MDA-MB-231, and MCF-10A) resulted in the reduction of IC50 values in a time- and dose-dependent mode with high specificity on MCF-7 (IC50 of 36 μM at 48 hours) against normal breast cell MCF-10A (no IC50 detected up to 180 μM at 72 hours)...
2016: Drug Design, Development and Therapy
Sujiraporn Pakchuen, Mai Ishibashi, Emi Takakusagi, Katsuhiko Shirahige, Takashi Sutani
At the onset of anaphase, a protease called separase breaks the link between sister chromatids by cleaving the cohesin subunit Scc1. This irreversible step in the cell cycle is promoted by degradation of the separase inhibitor, securin, and polo-like kinase (Plk) 1-dependent phosphorylation of the Scc1 subunit. Plk could recognize substrates through interaction between its phosphopeptide interaction domain, the polo-box domain, and a phosphorylated priming site in the substrate, which has been generated by a priming kinase beforehand...
August 12, 2016: Journal of Biological Chemistry
Christina Helmke, Monika Raab, Franz Rödel, Yves Matthess, Thomas Oellerich, Ranadip Mandal, Mourad Sanhaji, Henning Urlaub, Claus Rödel, Sven Becker, Klaus Strebhardt
Upon interaction of the CD95 receptor with its ligand, sequential association of the adaptor molecule FADD (MORT1), pro-forms of caspases-8/10, and the caspase-8/10 regulator c-FLIP leads to the formation of a death-inducing signaling complex. Here, we identify polo-like kinase (Plk) 3 as a new interaction partner of the death receptor CD95. The enzymatic activity of Plk3 increases following interaction of the CD95 receptor with its ligand. Knockout (KO) or knockdown of caspase-8, CD95 or FADD prevents activation of Plk3 upon CD95 stimulation, suggesting a requirement of a functional DISC for Plk3 activation...
August 2016: Cell Research
Eric Polley, Mark Kunkel, David Evans, Thomas Silvers, Rene Delosh, Julie Laudeman, Chad Ogle, Russell Reinhart, Michael Selby, John Connelly, Erik Harris, Nicole Fer, Dmitriy Sonkin, Gurmeet Kaur, Anne Monks, Shakun Malik, Joel Morris, Beverly A Teicher
BACKGROUND: Small cell lung carcinoma (SCLC) is an aggressive, recalcitrant cancer, often metastatic at diagnosis and unresponsive to chemotherapy upon recurrence, thus it is challenging to treat. METHODS: Sixty-three human SCLC lines and three NSCLC lines were screened for response to 103 US Food and Drug Administration-approved oncology agents and 423 investigational agents. The investigational agents library was a diverse set of small molecules that included multiple compounds targeting the same molecular entity...
October 2016: Journal of the National Cancer Institute
Arpron Leesombun, Sookruetai Boonmasawai, Naomi Shimoda, Yoshifumi Nishikawa
Herbal medicines and natural herb extracts are widely used as alternative treatments for various parasitic diseases, and such extracts may also have potential to decrease the side effects of the standard regimen drugs used to treat toxoplasmosis (sulfadiazine-pyrimethamine combination). We evaluated how effective the Thai piperaceae plants Piper betle, P. nigrum and P. sarmentosum are against Toxoplasma gondii infection in vitro and in vivo. Individually, we extracted the piperaceae plants with ethanol, passed them through a rotary evaporator and then lyophilized them to obtain crude extracts for each one...
2016: PloS One
Suyang Zhang, Leifu Chang, Claudio Alfieri, Ziguo Zhang, Jing Yang, Sarah Maslen, Mark Skehel, David Barford
In eukaryotes, the anaphase-promoting complex (APC/C, also known as the cyclosome) regulates the ubiquitin-dependent proteolysis of specific cell-cycle proteins to coordinate chromosome segregation in mitosis and entry into the G1 phase. The catalytic activity of the APC/C and its ability to specify the destruction of particular proteins at different phases of the cell cycle are controlled by its interaction with two structurally related coactivator subunits, Cdc20 and Cdh1. Coactivators recognize substrate degrons, and enhance the affinity of the APC/C for its cognate E2 (refs 4-6)...
May 12, 2016: Nature
Rahul Singh, Rachel Beasley, Thavy Long, Conor R Caffrey
Neglected tropical diseases, especially those caused by helminths, constitute some of the most common infections of the world's poorest people. Amongst these, schistosomiasis (bilharzia or 'snail fever'), caused by blood flukes of the genus Schistosoma, ranks second only to malaria in terms of human impact: two hundred million people are infected and close to 800 million are at risk of infection. Drug screening against helminths poses unique challenges: the parasite cannot be cloned and is difficult to target using gene knockouts or RNAi...
April 7, 2016: IEEE/ACM Transactions on Computational Biology and Bioinformatics
Manyi Ji, Ping Li, Nan Sheng, Lanlan Liu, Hong Pan, Ce Wang, Lintao Cai, Yifan Ma
Small interference RNA (siRNA)-based therapy holds great potential for cancer treatment. However, its clinical application remains unsatisfied due to the lack of a safe and effective RNA delivery system. Aberrantly elevated sialyation on cell membrane has been reported as an attractive target for cancer diagnosis and therapy. In this study, phenylboronic acid (PBA) was conjugated onto low molecular weight polyethylenimine (PEI1.8k) to generate amphiphilic PBA-grafted PEI1.8k (PEI-PBA) nanovector, which was designed to facilitate cancer-targeted RNA delivery through the recognition of sialic structures on a cancer cell membrane...
April 20, 2016: ACS Applied Materials & Interfaces
Olga O Nerusheva, Bungo Akiyoshi
Kinetochores are macromolecular machines that drive eukaryotic chromosome segregation by interacting with centromeric DNA and spindle microtubules. While most eukaryotes possess conventional kinetochore proteins, evolutionarily distant kinetoplastid species have unconventional kinetochore proteins, composed of at least 19 proteins (KKT1-19). Polo-like kinase (PLK) is not a structural kinetochore component in either system. Here, we report the identification of an additional kinetochore protein, KKT20, in Trypanosoma brucei...
March 2016: Open Biology
Shiv Kumar, Ashish Ranjan Sharma, Garima Sharma, Chiranjib Chakraborty, Jaebong Kim
PLK-1 is a key player in the eukaryotic cell cycle. Cell cycle progression is precisely controlled by cell cycle regulatory kinases. PLK-1 is a mitotic kinase that actively regulates the G2/M transition, mitosis, mitotic exit, and cytokinesis. During cell cycle progression, PLK-1 controls various events related to the cell cycle maturation, directly and/or indirectly. On the contrary, aberrant expression of PLK-1 is strongly associated with tumorigenesis and its poor prognosis. The misexpression of PLK-1 causes the abnormalities including aneuploidy, mitotic defects, leading to tumorigenesis through inhibiting the p53 and pRB genes...
April 2016: Biochimica et Biophysica Acta
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