A Cell Proliferation and Chromosomal Instability Signature in Anaplastic Thyroid Carcinoma

Salvatore, Giuliana; Nappi, Tito Claudio; Salerno, Paolo; Jiang, Yuan; Garbi, Corrado; Ugolini, Clara; Miccoli, Paolo; Basolo, Fulvio; Castellone, Maria Domenica; Cirafici, Anna Maria; Melillo, Rosa Marina; Bittner, Michael; Santoro, Massimo

doi:10.1158/0008-5472.can-07-1887

Cited by 166 publications

(148 citation statements)

References 40 publications

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“…20,21 Y/CCAAT is Enriched in Promoters of 'Cancer' Genes Analysis of transcriptome profiles during cellular transformation identified the Y/CCAAT box as over-represented in promoters of genes overexpressed in diverse types of cancers, breast, colon, thyroid, prostate and leukemias. [22][23][24][25][26][27][28][29] Treating cells with cytotoxic drugs, or overexpressing growth suppressors, led to the downregulation of genes with CCAAT in their promoters. 30,31 However, it is important to remark that these exercises were performed with matrices included in TRANSFAC and JASPAR; hence, they could be highly biased, as the lists of transcription factor-binding sites (TFBS) present in databases certainly do not recapitulate all possible TF-binding sequences.…”

Section: Y and Ccaat: Two Names One Entitymentioning

confidence: 99%

Targeting the Y/CCAAT box in cancer: YB-1 (YBX1) or NF-Y?

Dolfini

Mantovani

2013

Cell Death Differ

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The Y box is an important sequence motif found in promoters and enhancers containing a CCAAT box -one of the few elements enriched in promoters of large sets of genes overexpressed in cancer. The search for the transcription factor(s) acting on it led to the biochemical purification of the nuclear factor Y (NF-Y) heterotrimer, and to the cloning -through the screening of expression libraries -of Y box-binding protein 1 (YB-1), an oncogene, overexpressed in aggressive tumors and associated with drug resistance. These two factors have been associated with Y/CCAAT-dependent activation of numerous growth-related genes, notably multidrug resistance protein 1. We review two decades of data indicating that NF-Y ultimately acts on Y/CCAAT in cancer cells, a notion recently confirmed by genome-wide data. Other features of YB-1, such as post-transcriptional control of mRNA biology, render it important in cancer biology.

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Section: Y and Ccaat: Two Names One Entitymentioning

confidence: 99%

Targeting the Y/CCAAT box in cancer: YB-1 (YBX1) or NF-Y?

Dolfini

Mantovani

2013

Cell Death Differ

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“…Although derived from follicular epithelium of the thyroid gland, ATC cells do not retain any biological feature of the original cell type as a result of multiple mutational events leading to dedifferentiation. A number of gene expression studies in ATC yielded evidence of the upregulation of genes involved in cell cycle progression and chromosome segregation, among which were the Aurora kinases (Salvatore et al 2007, Wiseman et al 2007, Rusinek et al 2011. In particular, Aurora-A has been identified among the most frequently and strongly overexpressed proteins in ATC, and high expression of Aurora-B has been also reported (Sorrentino et al 2005, Ulisse et al 2006, Wiseman et al 2007.…”

Section: Introductionmentioning

confidence: 99%

Effects of selective inhibitors of Aurora kinases on anaplastic thyroid carcinoma cell lines

Baldini¹,

Tuccilli²,

Prinzi³

et al. 2014

Endocrine Related Cancer

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Aurora kinases are serine/threonine kinases that play an essential role in cell division. Their aberrant expression and/or function induce severe mitotic abnormalities, resulting in either cell death or aneuploidy. Overexpression of Aurora kinases is often found in several malignancies, among which is anaplastic thyroid carcinoma (ATC). We have previously demonstrated the in vitro efficacy of Aurora kinase inhibitors in restraining cell growth and survival of different ATC cell lines. In this study, we sought to establish which Aurora might represent the preferential drug target for ATC. To this end, the effects of two selective inhibitors of Aurora-A (MLN8237) and Aurora-B (AZD1152) on four human ATC cell lines (CAL-62, BHT-101, 8305C, and 8505C) were analysed. Both inhibitors reduced cell proliferation in a time-and dose-dependent manner, with IC 50 ranges of 44.3-134.2 nM for MLN8237 and of 9.2-461.3 nM for AZD1152. Immunofluorescence experiments and time-lapse videomicroscopy yielded evidence that each inhibitor induced distinct mitotic phenotypes, but both of them prevented the completion of cytokinesis. As a result, poliploidy increased in all AZD1152-treated cells, and in two out of four cell lines treated with MLN8237. Apoptosis was induced in all the cells by MLN8237, and in BHT-101, 8305C, and 8505C by AZD1152, while CAL-62 exposed to AZD1152 died through necrosis after multiple rounds of endoreplication. Both inhibitors were capable of blocking anchorage-independent cell growth. In conclusion, we demonstrated that either Aurora-A or Aurora-B might represent therapeutic targets for the ATC treatment, but inhibition of Aurora-A appears more effective for suppressing ATC cell proliferation and for inducing the apoptotic pathway.

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“…However, mechanistic insights into the regulation of SAC genes remain poorly understood. Using microarray analyses, at least two independent studies have identified UBE2C as a putative transcriptional repression target of p53 (11,27). Besides being an important gene in the spindle assembly checkpoint pathway, UBE2C has also been well implicated in multiple cancers (28).…”

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confidence: 99%

E2 Ubiquitin-conjugating Enzyme, UBE2C Gene, Is Reciprocally Regulated by Wild-type and Gain-of-Function Mutant p53

Bajaj

Alam

Roy

et al. 2016

Journal of Biological Chemistry

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Spindle assembly checkpoint governs proper chromosomal segregation during mitosis to ensure genomic stability. At the cellular level, this event is tightly regulated by UBE2C, an E2 ubiquitin-conjugating enzyme that donates ubiquitin to the anaphase-promoting complex/cyclosome. This, in turn, facilitates anaphase-onset by ubiquitin-mediated degradation of mitotic substrates. UBE2C is an important marker of chromosomal instability and has been associated with malignant growth. However, the mechanism of its regulation is largely unexplored. In this study, we report that UBE2C is transcriptionally activated by the gain-of-function (GOF) mutant p53, although it is transcriptionally repressed by wild-type p53. We showed that wild-type p53-mediated inhibition of UBE2C is p21-E2F4-dependent and GOF mutant p53-mediated transactivation of UBE2C is NF-Y-dependent. We further explored that DNA damage-induced wild-type p53 leads to spindle assembly checkpoint arrest by repressing UBE2C, whereas mutant p53 causes premature anaphase exit by increasing UBE2C expression in the presence of 5-fluorouracil. Identification of UBE2C as a target of wild-type and GOF mutant p53 further highlights the contribution of p53 in regulation of spindle assembly checkpoint.

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A Cell Proliferation and Chromosomal Instability Signature in Anaplastic Thyroid Carcinoma

Cited by 166 publications

References 40 publications

Targeting the Y/CCAAT box in cancer: YB-1 (YBX1) or NF-Y?

Targeting the Y/CCAAT box in cancer: YB-1 (YBX1) or NF-Y?

Effects of selective inhibitors of Aurora kinases on anaplastic thyroid carcinoma cell lines

E2 Ubiquitin-conjugating Enzyme, UBE2C Gene, Is Reciprocally Regulated by Wild-type and Gain-of-Function Mutant p53

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