scholarly journals PIGN spatiotemporally regulates the spindle assembly checkpoint proteins in leukemia transformation and progression

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Emmanuel K. Teye ◽  
Shasha Lu ◽  
Fangyuan Chen ◽  
Wenrui Yang ◽  
Thomas Abraham ◽  
...  
Keyword(s):  
Chromosomal Instability ◽  
Spindle Assembly Checkpoint ◽  
Spindle Assembly ◽  
Mitotic Checkpoint ◽  
Vital Role ◽  
The Novel ◽  
Checkpoint Activation ◽  
Checkpoint Proteins ◽  
Mitotic Kinase ◽  
Related Proteins

AbstractPhosphatidylinositol glycan anchor biosynthesis class N (PIGN) has been linked to the suppression of chromosomal instability. The spindle assembly checkpoint complex is responsible for proper chromosome segregation during mitosis to prevent chromosomal instability. In this study, the novel role of PIGN as a regulator of the spindle assembly checkpoint was unveiled in leukemic patient cells and cell lines. Transient downregulation or ablation of PIGN resulted in impaired mitotic checkpoint activation due to the dysregulated expression of spindle assembly checkpoint-related proteins including MAD1, MAD2, BUBR1, and MPS1. Moreover, ectopic overexpression of PIGN restored the expression of MAD2. PIGN regulated the spindle assembly checkpoint by forming a complex with the spindle assembly checkpoint proteins MAD1, MAD2, and the mitotic kinase MPS1. Thus, PIGN could play a vital role in the spindle assembly checkpoint to suppress chromosomal instability associated with leukemic transformation and progression.

scholarly journals PIGN Spatiotemporally Regulates the Spindle Assembly Checkpoint Proteins in Myelodysplastic Syndromes

2020 ◽  
Author(s):  
Emmanuel Teye ◽  
Shasha Lu ◽  
Fangyuan Chen ◽  
Wenrui Yang ◽  
Thomas Abraham ◽  
...  
Keyword(s):  
Myelodysplastic Syndromes ◽  
Chromosomal Instability ◽  
Spindle Assembly Checkpoint ◽  
Spindle Assembly ◽  
Mitotic Checkpoint ◽  
Vital Role ◽  
Checkpoint Activation ◽  
Checkpoint Proteins ◽  
Mitotic Kinase ◽  
Related Proteins

Abstract Phosphatidylinositol glycan anchor biosynthesis class N (PIGN) has been previously linked to the suppression of chromosomal instability. The spindle assembly checkpoint complex is responsible for proper chromosome segregation during mitosis to prevent chromosomal instability. In this study, the novel role of PIGN as a regulator of the spindle assembly checkpoint was unveiled in leukemic patient cells and cell lines. Transient downregulation or ablation of PIGN resulted in impaired mitotic checkpoint activation due to the dysregulated expression of spindle assembly checkpoint-related proteins including MAD1, MAD2, BUBR1, and MPS1. Moreover, ectopic overexpression of PIGN restored the expression of MAD2. PIGN regulated the spindle assembly checkpoint by forming a complex with the spindle assembly checkpoint proteins MAD1, MAD2, and the mitotic kinase MPS1. Thus, PIGN could play a vital role in the spindle assembly checkpoint to suppress chromosomal instability associated with the leukemic transformation of myelodysplastic syndromes.

scholarly journals Explaining the oligomerization properties of the spindle assembly checkpoint protein Mad2

2005 ◽  
Vol 360 (1455) ◽  
pp. 637-648 ◽  
Author(s):  
Anna DeAntoni ◽  
Valeria Sala ◽  
Andrea Musacchio
Keyword(s):  
Spindle Assembly Checkpoint ◽  
Spindle Assembly ◽  
Mitotic Checkpoint ◽  
Checkpoint Activation ◽  
Anaphase Onset ◽  
Open Conformation ◽  
Chromosome Attachment ◽  
A Subunit ◽  
Mitotic Checkpoint Complex ◽  
Spindle Assembly Checkpoint Protein

Mad2 is an essential component of the spindle assembly checkpoint (SAC), a molecular device designed to coordinate anaphase onset with the completion of chromosome attachment to the spindle. Capture of chromosome by microtubules occur on protein scaffolds known as kinetochores. The SAC proteins are recruited to kinetochores in prometaphase where they generate a signal that halts anaphase until all sister chromatid pairs are bipolarly oriented. Mad2 is a subunit of the mitotic checkpoint complex, which is regarded as the effector of the spindle checkpoint. Its function is the sequestration of Cdc20, a protein required for progression into anaphase. The function of Mad2 in the checkpoint correlates with a dramatic conformational rearrangement of the Mad2 protein. Mad2 adopts a closed conformation (C-Mad2) when bound to Cdc20, and an open conformation (O-Mad2) when unbound to this ligand. Checkpoint activation promotes the conversion of O-Mad2 to Cdc20-bound C-Mad2. We show that this conversion requires a C-Mad2 template and we identify this in Mad1-bound Mad2. In our proposition, Mad1-bound C-Mad2 recruits O-Mad2 to kinetochores, stimulating Cdc20 capture, implying that O-Mad2 and C-Mad2 form dimers. We discuss Mad2 oligomerization and link our discoveries to previous observations related to Mad2 oligomerization.

scholarly journals Aneuploid abortion correlates positively with MAD1 overexpression and miR-125b down-regulation

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Juan Zhao ◽  
Hui Li ◽  
Guangxin Chen ◽  
Lijun Du ◽  
Peiyan Xu ◽  
...  
Keyword(s):  
Chromosome Segregation ◽  
Spindle Assembly Checkpoint ◽  
Mitotic Checkpoint ◽  
Early Embryo ◽  
Vital Role ◽  
Control Group ◽  
Embryo Abortion ◽  
Protein Levels ◽  
Mitotic Checkpoint Complex

Abstract Background Aneuploidy is the most frequent cause of early-embryo abortion. Any defect in chromosome segregation would fail to satisfy the spindle assembly checkpoint (SAC) during mitosis, halting metaphase and causing aneuploidy. The mitotic checkpoint complex (MCC), comprising MAD1, MAD2, Cdc20, BUBR1 and BUB3, plays a vital role in SAC activation. Studies have confirmed that overexpression of MAD2 and BUBR1 can facilitate correct chromosome segregation and embryo stability. Research also proves that miR-125b negatively regulates MAD1 expression by binding to its 3′UTR. However, miR-125b, Mad1 and Bub3 gene expression in aneuploid embryos of spontaneous abortion has not been reported to date. Methods In this study, embryonic villi from miscarried pregnancies were collected and divided into two groups (aneuploidy and euploidy) based on High-throughput ligation-dependent probe amplification (HLPA) and Fluorescence in situ hybridization (FISH) analyses. RNA levels of miR-125b, MAD1 and BUB3 were detected by Quantitative real-time PCR (qRT-PCR); protein levels of MAD1 and BUB3 were analysed by Western blotting. Results statistical analysis (p < 0.05) showed that miR-125b and BUB3 were significantly down-regulated in the aneuploidy group compared to the control group and that MAD1 was significantly up-regulated. Additionally, the MAD1 protein level was significantly higher in aneuploidy abortion villus, but BUB3 protein was only mildly increased. Correlation analysis revealed that expression of MAD1 correlated negatively with miR-125b. Conclusion These results suggest that aneuploid abortion correlates positively with MAD1 overexpression, which might be caused by insufficient levels of miR-125b. Taken together, our findings first confirmed the negative regulatory mode between MAD1 and miR-125b, providing a basis for further mechanism researches in aneuploid abortion.

scholarly journals Loss of Kif18A Results in Spindle Assembly Checkpoint Activation at Microtubule-Attached Kinetochores

2018 ◽  
Vol 28 (17) ◽  
pp. 2685-2696.e4 ◽  
Author(s):  
Louise M.E. Janssen ◽  
Tessa V. Averink ◽  
Vincent A. Blomen ◽  
Thijn R. Brummelkamp ◽  
René H. Medema ◽  
...  
Keyword(s):  
Spindle Assembly Checkpoint ◽  
Spindle Assembly ◽  
Checkpoint Activation

scholarly journals Retracted: Three BUB1 and BUBR1/MAD3-related spindle assembly checkpoint proteins are required for accurate mitosis in Arabidopsis

2014 ◽  
Vol 205 (1) ◽  
pp. 202-215 ◽  
Author(s):  
Laetitia Paganelli ◽  
Marie-Cécile Caillaud ◽  
Michaël Quentin ◽  
Isabelle Damiani ◽  
Benjamin Govetto ◽  
...  
Keyword(s):  
Spindle Assembly Checkpoint ◽  
Spindle Assembly ◽  
Checkpoint Proteins

scholarly journals Use of the Novel Plk1 Inhibitor ZK-Thiazolidinone to Elucidate Functions of Plk1 in Early and Late Stages of Mitosis

2007 ◽  
Vol 18 (10) ◽  
pp. 4024-4036 ◽  
Author(s):  
Anna Santamaria ◽  
Rüdiger Neef ◽  
Uwe Eberspächer ◽  
Knut Eis ◽  
Manfred Husemann ◽  
...  
Keyword(s):  
Spindle Assembly Checkpoint ◽  
Spindle Assembly ◽  
Cleavage Furrow ◽  
The Novel ◽  
Mitotic Progression ◽  
Binding Partner ◽  
Molecule Inhibitor ◽  
Interaction Partners ◽  
Late Stages

Polo-like kinase 1 (Plk1) is a key regulator of mitotic progression and cell division in eukaryotes. It is highly expressed in tumor cells and considered a potential target for cancer therapy. Here, we report the discovery and application of a novel potent small-molecule inhibitor of mammalian Plk1, ZK-Thiazolidinone (TAL). We have extensively characterized TAL in vitro and addressed TAL specificity within cells by studying Plk1 functions in sister chromatid separation, centrosome maturation, and spindle assembly. Moreover, we have used TAL for a detailed analysis of Plk1 in relation to PICH and PRC1, two prominent interaction partners implicated in spindle assembly checkpoint function and cytokinesis, respectively. Specifically, we show that Plk1, when inactivated by TAL, spreads over the arms of chromosomes, resembling the localization of its binding partner PICH, and that both proteins are mutually dependent on each other for correct localization. Finally, we show that Plk1 activity is essential for cleavage furrow formation and ingression, leading to successful cytokinesis.

scholarly journals Spindle assembly checkpoint defects and chromosomal instability in head and neck squamous cell carcinoma

2003 ◽  
Vol 107 (1) ◽  
pp. 46-52 ◽  
Author(s):  
Khalid M. Minhas ◽  
Bhuvanesh Singh ◽  
Wei-wen Jiang ◽  
David Sidransky ◽  
Joseph A. Califano
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Head And Neck ◽  
Squamous Cell ◽  
Chromosomal Instability ◽  
Spindle Assembly Checkpoint ◽  
Spindle Assembly ◽  
Neck Squamous Cell Carcinoma

scholarly journals Disruption of Astral Microtubule Contact with the Cell Cortex Activates a Bub1, Bub3, and Mad3-dependent Checkpoint in Fission Yeast

2004 ◽  
Vol 15 (7) ◽  
pp. 3345-3356 ◽  
Author(s):  
Sylvie Tournier ◽  
Yannick Gachet ◽  
Vicky Buck ◽  
Jeremy S. Hyams ◽  
Jonathan B.A. Millar
Keyword(s):  
Actin Cytoskeleton ◽  
Fission Yeast ◽  
Spindle Assembly Checkpoint ◽  
Spindle Assembly ◽  
Yeast Cells ◽  
Cell Cortex ◽  
Checkpoint Proteins ◽  
Sister Chromatids ◽  
Astral Microtubule ◽  
Spindle Rotation

In animal and yeast cells, the mitotic spindle is aligned perpendicularly to the axis of cell division. This ensures that sister chromatids are separated to opposite sides of the cytokinetic actomyosin ring. In fission yeast, spindle rotation is dependent upon the interaction of astral microtubules with the cortical actin cytoskeleton. In this article, we show that addition of Latrunculin A, which prevents spindle rotation, delays the separation of sister chromatids and anaphase promoting complex-mediated destruction of spindle-associated Securin and Cyclin B. Moreover, we find that whereas sister kinetochore pairs normally congress to the spindle midzone before anaphase onset, this congression is disrupted when astral microtubule contact with the actin cytoskeleton is disturbed. By analyzing the timing of kinetochore separation, we find that this anaphase delay requires the Bub3, Mad3, and Bub1 but not the Mad1 or Mad2 spindle assembly checkpoint proteins. In agreement with this, we find that Bub1 remains associated with kinetochores when spindles are mispositioned. These data indicate that, in fission yeast, astral microtubule contact with the medial cell cortex is monitored by a subset of spindle assembly checkpoint proteins. We propose that this checkpoint ensures spindles are properly oriented before anaphase takes place.

scholarly journals The Spindle Assembly Checkpoint Regulates the Phosphorylation State of a Subset of DNA Checkpoint Proteins in Saccharomyces cerevisiae

2006 ◽  
Vol 26 (24) ◽  
pp. 9149-9161 ◽  
Author(s):  
Céline Clémenson ◽  
Marie-Claude Marsolier-Kergoat
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Dna Damage Response ◽  
Spindle Assembly Checkpoint ◽  
Spindle Checkpoint ◽  
Spindle Assembly ◽  
Dna Lesions ◽  
Checkpoint Proteins ◽  
Cell Responses ◽  
Spindle Assembly Checkpoints ◽  
Damage Response

ABSTRACT The DNA and the spindle assembly checkpoints play key roles in maintaining genomic integrity by coordinating cell responses to DNA lesions and spindle dysfunctions, respectively. These two surveillance pathways seem to operate mostly independently of one another, and little is known about their potential physiological connections. Here, we show that in Saccharomyces cerevisiae, the activation of the spindle assembly checkpoint triggers phosphorylation changes in two components of the DNA checkpoint, Rad53 and Rad9. These modifications are independent of the other DNA checkpoint proteins and are abolished in spindle checkpoint-defective mutants, hinting at specific functions for Rad53 and Rad9 in the spindle damage response. Moreover, we found that after UV irradiation, Rad9 phosphorylation is altered and Rad53 inactivation is accelerated when the spindle checkpoint is activated, which suggests the implication of the spindle checkpoint in the regulation of the DNA damage response.

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