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Yoshitaka Hiruma, Andre Koch, Shreya Dharadhar, Robbie P Joosten, Anastassis Perrakis
Monopolar spindle 1 (Mps1, also known as TTK) is a protein kinase crucial for ensuring that cell division progresses to anaphase only after all chromosomes are connected to spindle microtubules. Incomplete chromosomal attachment leads to abnormal chromosome counts in the daughter cells (aneuploidy), a condition common in many solid cancers. Therefore Mps1 is an established target in cancer therapy. Mps1 kinase inhibitors include reversine (2-(4-morpholinoanilino)-6-cyclohexylaminopurine), a promiscuous compound first recognized as an inhibitor of the Aurora B mitotic kinase...
October 3, 2016: Proteins
Irina Alimova, June Ng, Peter Harris, Diane Birks, Andrew Donson, Michael D Taylor, Nicholas K Foreman, Sujatha Venkataraman, Rajeev Vibhakar
Medulloblastoma is the most common type of malignant brain tumor that affects children. Although recent advances in chemotherapy and radiation have improved outcomes, high-risk patients perform poorly with significant morbidity. Gene expression profiling has revealed that monopolar spindle 1 (MPS1) (TTK1) is highly expressed in medulloblastoma patient samples compared to that noted in normal cerebellum. MPS1 is a key regulator of the spindle assembly checkpoint (SAC), a mitotic mechanism specifically required for proper chromosomal alignment and segregation...
September 12, 2016: Oncology Reports
Samer Shalaby, Olga Larkov, Netta-Li Lamdan, Orit Goldshmidt-Tran, Benjamin A Horwitz
Plant aromatic compounds provide signals and a nutrient source to pathogens, and also act as stressors. Structure-activity relationships suggest two pathways sensing these compounds in the maize pathogen Cochliobolus heterostrophus, one triggering a stress response, and one inducing enzymes for their degradation. Focusing on the stress pathway, we found that ferulic acid causes rapid appearance of TUNEL-positive nuclei, dispersion of histone H1:GFP, hyphal shrinkage, and eventually membrane damage. These hallmarks of programmed cell death (PCD) were not seen upon exposure to caffeic acid, a very similar compound...
September 15, 2016: Environmental Microbiology
M Kasim Diril, Xavier Bisteau, Mayumi Kitagawa, Matias J Caldez, Sheena Wee, Jayantha Gunaratne, Sang Hyun Lee, Philipp Kaldis
The Greatwall kinase/Mastl is an essential gene that indirectly inhibits the phosphatase activity toward mitotic Cdk1 substrates. Here we show that although Mastl knockout (MastlNULL) MEFs enter mitosis, they progress through mitosis without completing cytokinesis despite the presence of misaligned chromosomes, which causes chromosome segregation defects. Furthermore, we uncover the requirement of Mastl for robust spindle assembly checkpoint (SAC) maintenance since the duration of mitotic arrest caused by microtubule poisons in MastlNULL MEFs is shortened, which correlates with premature disappearance of the essential SAC protein Mad1 at the kinetochores...
September 2016: PLoS Genetics
Maria Del Mar Mora-Santos, America Hervas-Aguilar, Katharina Sewart, Theresa C Lancaster, John C Meadows, Jonathan B A Millar
The spindle assembly checkpoint (SAC) ensures that sister chromatids do not separate until all chromosomes are attached to spindle microtubules and bi-oriented. Spindle checkpoint proteins, including Mad1, Mad2, Mad3 (BubR1), Bub1, Bub3, and Mph1 (Mps1), are recruited to unattached and/or tensionless kinetochores. SAC activation catalyzes the conversion of soluble Mad2 (O-Mad2) into a form (C-Mad2) that binds Cdc20, BubR1, and Bub3 to form the mitotic checkpoint complex (MCC), a potent inhibitor of the anaphase-promoting complex (APC/C)...
October 10, 2016: Current Biology: CB
Mark D Gurden, Simon J Anderhub, Amir Faisal, Spiros Linardopoulos
Accurate chromosome segregation is dependent on the spindle assembly checkpoint (SAC). In current models, the key direct role of Aurora B in the SAC has been suggested to be to promote rapid kinetochore localisation of MPS1, allowing MPS1 to generate the checkpoint signal. However, Aurora B is also thought to play an indirect role in the SAC through the destabilisation of kinetochore-microtubule (KT-MT) attachments. Here, we demonstrate that Aurora B activity is not required for the kinetochore recruitment of the majority of SAC proteins...
July 18, 2016: Oncotarget
X Zhang, Y Ling, Y Guo, Y Bai, X Shi, F Gong, P Tan, Y Zhang, C Wei, X He, A Ramirez, X Liu, C Cao, H Zhong, Q Xu, R Z Ma
Targeting mitotic kinase monopolar spindle 1 (Mps1) for tumor therapy has been investigated for many years. Although it was suggested that Mps1 regulates cell viability through its role in spindle assembly checkpoint (SAC), the underlying mechanism remains less defined. In an endeavor to reveal the role of high levels of mitotic kinase Mps1 in the development of colon cancer, we unexpectedly found the amount of Mps1 required for cell survival far exceeds that of maintaining SAC in aneuploid cell lines. This suggests that other functions of Mps1 besides SAC are also employed to maintain cell viability...
2016: Cell Death & Disease
Joseph R Marquardt, Jennifer L Perkins, Kyle J Beuoy, Harold A Fisk
Faithful segregation of chromosomes to two daughter cells is regulated by the formation of a bipolar mitotic spindle and the spindle assembly checkpoint, ensuring proper spindle function. Here we show that the proper localization of the kinase Mps1 (monopolar spindle 1) is critical to both these processes. Separate elements in the Mps1 N-terminal extension (NTE) and tetratricopeptide repeat (TPR) domains govern localization to either the kinetochore or the centrosome. The third TPR (TPR3) and the TPR-capping helix (C-helix) are each sufficient to target Mps1 to the centrosome...
July 12, 2016: Proceedings of the National Academy of Sciences of the United States of America
Radoslaw Laufer, Sze-Wan Li, Yong Liu, Grace Ng, Yunhui Lang, Miklos Feher, Richard Brokx, Irina Beletskaya, Richard Hodgson, Guodong Mao, Olga Plotnikova, Donald E Awrey, Jacqueline M Mason, Xin Wei, Dan Chi-Chia Lin, Yi Che, Reza Kiarash, Brian Madeira, Graham C Fletcher, Tak W Mak, Mark R Bray, Henry W Pauls
TTK/Mps1 is a key kinase controlling progression of cell division via participation in the mitotic spindle assembly checkpoint and is overexpressed in a number of human cancers. Herein we report the discovery of 4-(4-aminopyrazolo[1,5-a][1,3,5]triazin-8-yl)benzamides as a potent, novel class of TTK inhibitors. The series was identified by means of bioisosteric replacement of the related imidazopyrazine and imidazopyridazine scaffolds. Optimization led to the identification of compounds with excellent potency (Ki=0...
August 1, 2016: Bioorganic & Medicinal Chemistry Letters
Guðjón Ólafsson, Peter H Thorpe
The spindle assembly checkpoint (SAC) is a key mechanism to regulate the timing of mitosis and ensure that chromosomes are correctly segregated to daughter cells. The recruitment of the Mad1 and Mad2 proteins to the kinetochore is normally necessary for SAC activation. This recruitment is coordinated by the SAC kinase Mps1, which phosphorylates residues at the kinetochore to facilitate binding of Bub1, Bub3, Mad1, and Mad2. There is evidence that the essential function of Mps1 is to direct recruitment of Mad1/2...
2016: G3: Genes—Genomes—Genetics
Motofumi Suzuki, Tohru Yamamori, Hironobu Yasui, Osamu Inanami
BACKGROUND/AIM: The monopolar spindle 1 (MPS1) is a serine/threonine kinase that plays an important role in spindle assembly checkpoint signaling. To determine the possible relationship between MPS1 inhibition and genotoxic stress responses, herein we examined whether MPS1 inhibition influences cellular susceptibility towards two genotoxic treatments, etoposide and ionizing radiation (IR). MATERIALS AND METHODS: Two murine tumour cell lines, SCCVII and EMT6, were used...
June 2016: Anticancer Research
Ching Yuan, Erick D Bothun, David R Hardten, Jakub Tolar, Linda K McLoon
One common complication of mucopolysaccharidosis I-Hurler (MPS1-H) is corneal clouding, which occurs despite current treatments, including bone marrow transplantation. Human corneas were obtained from a 14 year old subject with MPS1-H and visual disability from progressive corneal clouding despite a prior bone marrow transplant at age 2. This was compared to a cornea from a 17 year old donated to our eye bank after his accidental death. The corneas were analyzed microscopically after staining with Alcian blue, antibodies to collagen I, IV, VI, and α-smooth muscle actin...
July 2016: Experimental Eye Research
Sarah Saputo, Kaitlyn L Norman, Thomas Murante, Brooke N Horton, Jacinto De La Cruz Diaz, Louis DiDone, Jennifer Colquhoun, Jeremy W Schroeder, Lyle A Simmons, Anuj Kumar, Damian J Krysan
Although the analysis of genetic interactions and networks is a powerful approach to understanding biology, it has not been applied widely to the pathogenic yeast Candida albicans Here, we describe the use of both screening and directed genetic interaction studies based on complex haploinsufficiency to probe the function of the R: egulation of A: ce2 and M: orphogenesis (RAM) pathway in C. albicans A library of 5200 Tn7-mutagenized derivatives of a parental strain heterozygous at CBK1, the key kinase in the RAM pathway, was screened for alterations in serum-induced filamentation...
July 2016: Genetics
Pavithra Aravamudhan, Renjie Chen, Babhrubahan Roy, Janice Sim, Ajit P Joglekar
Recruitment of Spindle Assembly Checkpoint (SAC) proteins by an unattached kinetochore leads to SAC activation. This recruitment is licensed by the Mps1 kinase, which phosphorylates the kinetochore protein Spc105 at one or more of its six 'MELT' repeats. Spc105 then recruits the Bub3-Bub1 and Mad1-Mad2 complexes, which produce the inhibitory signal that arrests cell division. The strength of this signal depends, in part, on the number Bub3-Bub1 and Mad1-Mad2 molecules that Spc105 recruits. Therefore, regulation of this recruitment will influence SAC signaling...
May 11, 2016: Molecular Biology of the Cell
Samantha J Williams, Ariane Abrieu, Ana Losada
Centromeric chromatin containing the histone H3 variant centromere protein A (CENP-A) directs kinetochore assembly through a hierarchical binding of CENPs, starting with CENP-C and CENP-T. Centromeres are also the chromosomal regions where cohesion, mediated by cohesin, is most prominently maintained in mitosis. While most cohesin dissociates from chromosome arms in prophase, Shugoshin 1 (Sgo1) prevents this process at centromeres. Centromeric localization of Sgo1 depends on histone H2A phosphorylation by the kinase Bub1, but whether additional interactions with kinetochore components are required for Sgo1 recruitment is unclear...
April 26, 2016: Chromosoma
America Hervas-Aguilar, Jonathan B A Millar
No abstract text is available yet for this article.
May 18, 2016: Cell Cycle
Jackellinne C Douétts-Peres, Marco Antônio L Cruz, Ricardo S Reis, Angelo S Heringer, Eduardo A G de Oliveira, Paula M Elbl, Eny I S Floh, Vanildo Silveira, Claudete Santa-Catarina
Somatic embryogenesis has been shown to be an efficient tool for studying processes based on cell growth and development. The fine regulation of the cell cycle is essential for proper embryo formation during the process of somatic embryogenesis. The aims of the present work were to identify and perform a structural and functional characterization of Mps1 and to analyze the effects of the inhibition of this protein on cellular growth and pro-embryogenic mass (PEM) morphology in embryogenic cultures of A. angustifolia...
2016: PloS One
Paolo Innocenti, Hannah L Woodward, Savade Solanki, Sébastien Naud, Isaac M Westwood, Nora Cronin, Angela Hayes, Jennie Roberts, Alan T Henley, Ross Baker, Amir Faisal, Grace Wing-Yan Mak, Gary Box, Melanie Valenti, Alexis De Haven Brandon, Lisa O'Fee, Harry Saville, Jessica Schmitt, Berry Matijssen, Rosemary Burke, Rob L M van Montfort, Florence I Raynaud, Suzanne A Eccles, Spiros Linardopoulos, Julian Blagg, Swen Hoelder
Monopolar spindle 1 (MPS1) plays a central role in the transition of cells from metaphase to anaphase and is one of the main components of the spindle assembly checkpoint. Chromosomally unstable cancer cells rely heavily on MPS1 to cope with the stress arising from abnormal numbers of chromosomes and centrosomes and are thus more sensitive to MPS1 inhibition than normal cells. We report the discovery and optimization of a series of new pyrido[3,4-d]pyrimidine based inhibitors via a structure-based hybridization approach from our previously reported inhibitor CCT251455 and a modestly potent screening hit...
April 28, 2016: Journal of Medicinal Chemistry
Joseph R Marquardt, Harold A Fisk
The kinetochore-associated kinase Mps1 controls the spindle assembly checkpoint, but the regulation of its kinetochore recruitment and activity is unclear. In this issue, Isokane et al. (2016. J. Cell Biol. show that interaction with and phosphorylation of its substrate, ARHGEF17, regulates Mps1 kinetochore retention, suggesting an autoregulated, timer-like mechanism.
March 14, 2016: Journal of Cell Biology
Mayumi Isokane, Thomas Walter, Robert Mahen, Bianca Nijmeijer, Jean-Karim Hériché, Kota Miura, Stefano Maffini, Miroslav Penchev Ivanov, Tomoya S Kitajima, Jan-Michael Peters, Jan Ellenberg
To prevent genome instability, mitotic exit is delayed until all chromosomes are properly attached to the mitotic spindle by the spindle assembly checkpoint (SAC). In this study, we characterized the function of ARHGEF17, identified in a genome-wide RNA interference screen for human mitosis genes. Through a series of quantitative imaging, biochemical, and biophysical experiments, we showed that ARHGEF17 is essential for SAC activity, because it is the major targeting factor that controls localization of the checkpoint kinase Mps1 to the kinetochore...
March 14, 2016: Journal of Cell Biology
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