Search results for " p14ARF"

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 …

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. …

Absence of germline CDKN2A mutation in Sicilian Patients with Familial Malignant Melanoma: could it be a population-specific genetic signature?

2015

Germline CDKN2A mutations have been described in 25% to 40% of melanoma families from several countries. Sicilian population is genetically different from the people of Europe and Northern Italy because of its historical background, therefore familial melanoma could be due to genes different from high-penetrance CDKN2A gene. Four hundred patients with cutaneous melanoma were observed in a 6-years period at the Plastic Surgery Unit of the University of Palermo. Forty-eight patients have met the criteria of the Italian Society of Human Genetics (SIGU) for the diagnosis of familial melanoma and were screened for CDKN2A and CDK4 mutations. Mutation testing revealed that none of the families car…

Molecular and immunohistochemical analysis of the prognostic value of cell-cycle regulators in urothelial neoplasms of the bladder.

2006

Abstract Objective To evaluate the prognostic and predictive value of molecular and immunohistochemical markers related to cell-cycle control in terms of recurrence, progression, and survival in urothelial neoplasms of the bladder (UNB). Patients and Methods Clinical and pathological findings of 84 patients with UNB were assessed. Homozygous deletion (HD) and promoter methylation of p14 ARF , p15 INK4B , p16 INK4A , loss of heterozygosity of the locus 9p21, p53 mutations, and immunohistochemical expression of p53, p16, p14, p21, p27, pRb, Ki67, MDM2, and cyclin D1 proteins were evaluated in relation to overall survival (OS), recurrence-free survival (RFS), and progression-free survival (PFS…

The tumor suppressor p14ARF hampers proliferation of aneuploid cells induced by CENP-E partial depletion

The Spindle Assembly Checkpoint (SAC) is a cellular surveillance mechanism that ensures faithfully segregation of chromosomes. Reduced expression of some of its components weakens the SAC and induces chromosome instability and aneuploidy, both hallmarks of tumor cells. Centromere Protein-E (CENP-E) is a crucial component of the SAC and facilitates kinetochore microtubule attachment required to achieve and maintain chromosome alignment. To investigate the possible role of p14ARF on aneuploid cells proliferation we induced aneuploidy in primary human fibroblasts (IMR90) and in near diploid tumor cells (HCT116) by partial depletion of CENP-E obtained by RNA interference. Our results show that …

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…

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…