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Mosaic Variegated Aneuploidy Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
TRIP13 helps sustain mitotic SAC by converting the mitotic checkpoint protein MAD2 from a closed (active) to an open (inactive) conformation in prometaphase, silences the mitotic checkpoint in metaphase through inactivation of MAD2 when all kinetochores are attached, and triggers anaphase onset. In addition, TRIP13 promotes early steps of DNA double-strand breaks (DSBs) repair process.
Clinical genetics
Published in C. Simon Herrington, Muir's Textbook of Pathology, 2020
In mitosis, the cell divides to produce two almost identical daughter cells. Both parent and daughter cells are diploid. The phases of mitosis are named interphase, prophase, prometaphase, metaphase, anaphase, and telophase (Figure 5.4).
Disease Prediction and Drug Development
Published in Arvind Kumar Bansal, Javed Iqbal Khan, S. Kaisar Alam, Introduction to Computational Health Informatics, 2019
Arvind Kumar Bansal, Javed Iqbal Khan, S. Kaisar Alam
Mitosis is a multiphase process. The main stages are: 1) prophase; 2) prometaphase; 3) metaphase; 4) anaphase and 5) telophase. In the prophase, the chromosome-strands called chromatids separate. However, the chromatids remain connected at the constricted region joining the chromatids. After that, chromatids undergo a condensation process on a bipolar fibrous material within a cell. This fibrous material is called mitotic spindle. During prometaphase, the nuclear envelope within a cell is divided into multiple fluid-filled fragments called a vesicle. These vesicles are divided eventually in daughter-cells. In the anaphase, the sister-chromatids separate abruptly. The spindle-poles separate using motor proteins. Mitosis ends with telophase when the separated chromosomes reach the poles of the spindle, and the chromosomes begin to decondense from the spindle. Telophase is followed by cytokinesis – the division of the cytoplasm into identical cells: cells having identical genetic composition.
Aurora kinase inhibitors: a patent review (2014-2020)
Published in Expert Opinion on Therapeutic Patents, 2021
Aurora kinase family includes three subtypes: named as Aurora A, B and C. They all possess a highly conserved C-terminal domain and an N-terminal domain but have differences in functionality [4]. In the cell cycle, Aurora A is responsible for mitotic entry, centrosome maturation, and separation, spindle assembly and spindle damage repair [5]. Aurora A is activated by ajuba at the beginning of the S phase and at G2/M transition its activity arrives at a peak to stimulate duplicated centrosomes to separate and initiate the mitotic entry [4]. Aurora A kinase activity depends on the phosphorylation status of a threonine residue (T288) located on the ‘activation loop’ of the enzyme. In prometaphase, Aurora A is targeted to microtubules by phosphorylating TPX2 to contribute to spindle assembly and bipolar spindle microtubule conformation [6]. In addition, Aurora A also has a variety of non-mitotic functions, such as DNA damage response (DDR) [7] and activation of epithelial–mesenchymal transition (EMT) reprograming [8]. Inhibition of Aurora A would result in uneven distribution of chromosomes to daughter cells and abnormal spindle structure, followed by aneuploidy [9].
Ultrastructure of colorectal adenocarcinoma and peritumoral tissue in untreated patients
Published in Ultrastructural Pathology, 2018
Hector L. Osorio, Hector J. Finol, L. Roschman Gonzalez, Carlos E. Sardiñas
Different ultrastructural alterations were found in epithelial cells of CAC (tumor). Initially changes were seen in mitochondrial morphology (Figure 1(a,b)). On the contrary, rough endoplasmic reticulum (RER) looked normal (Figure 1(a)). Furthermore, in addition to cells with normal looking RER, other cells appeared with RER alterations consisting of swollen cisternae (Figure 1(b)) and rests of RER participating in the formation of autophagosomes (Figure 1(c)). In relation to the Golgi apparatus, there was a significant cisternae reduction and its presence was observed in areas with autophagosomes (Figure 1(d)). In these cells, nucleus exhibited a normal ultrastructure (Figure 1(a,d)). Nevertheless, other cells showed nuclei with deep invaginations and nucleoli with a very electron dense aspect (Figure 3(c)). In advanced stages of degeneration and necrosis, nuclei presented heterochromatin alteration and loss of nuclear envelope with nuclear matrix extraction (Figure 2(a,b)). Mitochondrial and RER swelling was also seen in the prometaphase of some dividing cells (Figure 2(c)), In this case, a chromosome still covered with rests of nuclear envelope was found. In addition, loss of intercellular desmosomes was detected (Figure 2(d)), the altered cells also presented mitochondrial swelling, abundant polysomes and the disappearance of RER. Note also the presence of multivesicular bodies.
Design of new disubstituted imidazo[1,2-b]pyridazine derivatives as selective Haspin inhibitors. Synthesis, binding mode and anticancer biological evaluation
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Jonathan Elie, Omid Feizbakhsh, Nathalie Desban, Béatrice Josselin, Blandine Baratte, Amandine Bescond, Julien Duez, Xavier Fant, Stéphane Bach, Dominique Marie, Matthieu Place, Sami Ben Salah, Agnes Chartier, Sabine Berteina-Raboin, Apirat Chaikuad, Stefan Knapp, Fabrice Carles, Pascal Bonnet, Frédéric Buron, Sylvain Routier, Sandrine Ruchaud
We next tested in cells the functional effects of compounds 12, 14, 21 and 22 as well as compounds 5 and 29 as reference and negative controls, respectively. We monitored and quantified Haspin activity by immunofluorescence and image analysis in U-2 OS cells following the phosphorylation of Threonine 3 of Histone H3 (H3T3ph) as a specific marker (Figure 5). Cells were treated with 0.5 µM of the various compounds for 24 h. As shown in Figure 5(A), treatment of cells with compounds 5, 12, 14, 21 and 22 greatly reduced the H3T3ph signal in selected prometaphase/metaphase cells. We noted that typical chromosome misalignment defects were observed as previously reported in Haspin depletion studies14. Quantification of the H3T3ph signal vs DAPI is represented in Figure 5(B,C). Compounds 5, 21 and 12 showed the strongest effect on cellular Haspin activity with only 2.5, 2.4 and 1.9% of H3T3ph signal remaining in prometaphase cells, respectively. This effect was slightly milder with compound 22- and 14-treated cells where 10.7 and 11.9% of H3T3p signal respectively remained (Figure 5(B,C)). The negative compound 29 showed a value similar to that of the DMSO control. A similar experiment performed on cells treated with a lower dose of 0.05 µM of compounds for 24 h revealed that cellular Haspin activity was still inhibited by more than 80% by compounds 5, 12, 21 and 22 (Supplementary Figure S5). These results showed that all tested compounds are highly cell penetrant and inhibit endogenous Haspin kinase. A comparison of their effects showed that compounds 5, 12 and 21 were the most efficient at reducing cellular Haspin activity.