Search results for "MAD2"
showing 10 items of 18 documents
MAD2 depletion triggers premature cellular senescence in human primary fibroblasts by activating a P53 pathway preventing aneuploid cells propagation.
2012
The spindle assembly checkpoint (SAC) is a cellular surveillance mechanism that ensures faithful chromosome segregation during mitosis and its failure can result in aneuploidy. Previously, it was suggested that reduction of the MAD2 gene, encoding a major component of the SAC, induced aneuploidy in human tumor cells. However, tumor cell lines contain multiple mutations that might affect or exacerbate the cellular response to Mad2 depletion. Thus, the scenario resulting by Mad2 depletion in primary human cells could be different and more complex that the one depicted so far. We used primary human fibroblasts (IMR90) and epithelial breast cells (MCF10A) to gain further insight on the effects …
MECHANISMS OF CHROMOSOMAL INSTABILITY: RELATIONSHIP BETWEEN TUMOR SUPPRESSORS AND SAC GENES
2017
Caratteristica comune di molti tumori solidi è l’aneuploidia, conseguenza dell’instabilità cromosomica (CIN). Tuttavia non sono ancora chiari i meccanismi alla base dell’aneuploidia e i percorsi che permettono la sua tolleranza. Lo Spindle Assembly Checkpoint (SAC) è un meccanismo di sorveglianza cellulare che controlla la stabilità genomica durante la mitosi. Alterazioni nei membri del SAC generano aneuploidia, ma non è ancora chiaro se questi difetti sono sufficienti per promuovere la tumori-genesi. In questo processo, infatti, il contesto genetico della cellula gioca un ruolo importante. È risaputo che i difetti di p53 aiutano le cellule a proliferare velocemente tollerando la CIN. Al co…
Growth and differentiation factor 11 (GDF11): Functions in the regulation of erythropoiesis and cardiac regeneration
2015
International audience; Members of the TGF-β superfamily transduce their signals through type I and II receptor serine/threonine kinases. The binding of activins to activin type IIA (ActRIIA) or type IIB (ActRIIB) receptors induces the recruitment and phosphorylation of an activin type I receptor (ALK4 and/or ALK7), which then phosphorylates the Smad2 and Smad3 intracellular signaling proteins. The regulation of members of the TGF-β family is known to be complex, because many proteins able to bind the ligands and inhibit their activities have been identified. Growth and differentiation factor 11 (Gdf11) belongs to the TGF-β family. GDF11, like other members of the TGF-β superfamily, is prod…
p14ARF re-expression induces apoptosis in aneuploid HCT116 cells
2012
Weakening the Spindle Assembly Checkpoint by reduced expression of its components such as MAD2, BubR1 and MPS1 induces chromosome instability and aneuploidy both hallmarks of cancer cells. p14ARF that is found frequently altered in human cancers, is overexpressed in response to oncogenic stimuli to stabilize p53 halting cell progression. Previously, we determined that lack or reduced expression of p14ARF is involved in the maintenance of aneuploid cells suggesting that it could be part of a pathway controlling proliferation of aneuploidy cells. To investigate further this aspect of p14ARF function it was ectopically expressed in HCT116 cells, a stable near diploid cell line, after MAD2 depl…
RNA interference of MAD2 and BUBR1 genes causes mitotic spindle alterations, aneuploidy and cell cycle arrest p53-dependent.
2009
The Spindle Assembly Checkpoint (SAC) is a cellular surveillance mechanism that functions to ensure faithful chromosome segregation during mitosis. Failure of this checkpoint or alteration in expression of SAC proteins (MAD2, BUB1, BUBR1 and others) can result in aneuploidy, a state of having abnormal numbers of chromosomes. MAD2 haploinsufficiency resulted in aneuploidy in MEFs and colon cancer cells in culture. Thus, spindle checkpoint components might have additional functions not-checkpoint-related functions that when disrupted contribute to tumorigenesis. Here we investigated the effects of MAD2 or BUBR1 transcriptional silencing in HCT-116 cells. Transient reduction of MAD2 (40%) and …
p14(ARF) Prevents Proliferation of Aneuploid Cells by Inducing p53-Dependent Apoptosis.
2014
Weakening the Spindle Assembly Checkpoint by reduced expression of its components induces chromosome instability and aneuploidy that are hallmarks of cancer cells. The tumor suppressor p14(ARF) is overexpressed in response to oncogenic stimuli to stabilize p53 halting cell progression. Previously, we found that lack or reduced expression of p14(ARF) is involved in the maintenance of aneuploid cells in primary human cells, suggesting that it could be part of a pathway controlling their proliferation. To investigate this aspect further, p14(ARF) was ectopically expressed in HCT116 cells after depletion of the Spindle Assembly Checkpoint MAD2 protein that was used as a trigger for aneuploidy. …
Systemic blockade of ACVR2B ligands protects myocardium from acute ischemia-reperfusion injury
2019
Activin A and myostatin, members of the transforming growth factor (TGF)-β superfamily of secreted factors, are potent negative regulators of muscle growth, but their contribution to myocardial ischemia-reperfusion (IR) injury is not known. The aim of this study was to investigate if activin 2B (ACVR2B) receptor ligands contribute to myocardial IR injury. Mice were treated with soluble ACVR2B decoy receptor (ACVR2B-Fc) and subjected to myocardial ischemia followed by reperfusion for 6 or 24 h. Systemic blockade of ACVR2B ligands by ACVR2B-Fc was protective against cardiac IR injury, as evidenced by reduced infarcted area, apoptosis, and autophagy and better preserved LV systolic function fo…
Simultaneous reduction of MAD2 and BUBR1 expression induces mitotic spindle alterations associated with p53 dependent cell cycle arrest and death
2014
Most human tumors are characterized by aneuploidy that is believed to be the consequence of chromosomal instability (CIN). The mechanism(s) leading to aneuploidy and the pathways that allow its tolerance are not completely understood. The Spindle Assembly Checkpoint (SAC) is a cellular surveillance mechanism working during mitosis, and alterations of genes that encode components of the SAC weakening the mitotic checkpoint, induce aneuploidy by chromosome mis-segregation. We induced aneuploidy in near-diploid tumor cells by simultaneous depletion of the SAC proteins MAD2 and BUBR1 by RNA interference in the attempt to gain further insight on the cellular responses to aneuploidy. Individual r…
Exploring organ-specific features of fibrogenesis using murine precision-cut tissue slices
2019
Fibrosis is the hallmark of pathologic tissue remodelling in most chronic diseases. Despite advances in our understanding of the mechanisms of fibrosis, it remains uncured. Fibrogenic processes share conserved core cellular and molecular pathways across organs. In this study, we aimed to elucidate shared and organ-specific features of fibrosis using murine precision-cut tissue slices (PCTS) prepared from small intestine, liver and kidneys. PCTS displayed substantial differences in their baseline gene expression profiles: 70% of the extracellular matrix (ECM)-related genes were differentially expressed across the organs. Culture for 48 h induced significant changes in ECM regulation and trig…