Mutations of TP53 induce loss of DNA methylation and amplification of the TROP1 gene

Nasr, Ashraf F; Nutini, Michele; Palombo, Barbara; Guerra, Emanuela; Alberti, Saverio

doi:10.1038/sj.onc.1206248

Cited by 36 publications

(28 citation statements)

References 40 publications

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“…Indeed, TROP1 gene methylation is maintained in a WT p53 background but is lost in a p53 mutant (29), presumably affecting DNMT1 interaction. Furthermore, in hepatocellular carcinoma, methylation-mediated inactivation of p14ARF was found to be restricted to WT p53 (30).…”

Section: Discussionmentioning

confidence: 99%

Human maintenance DNA (cytosine-5)-methyltransferase and p53 modulate expression of p53-repressed promoters

Estève

Chin²,

Pradhan³

2005

Proc. Natl. Acad. Sci. U.S.A.

149

127

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DNA (cytosine-5)-methyltransferase (DNMT) 1 participates in transcriptional repression of genes by methylation-dependent and -independent mechanisms. Here, DNMT1 is shown to bind p53 and colocalize in the nucleus. DNMT1-mediated methylation is stimulated by p53 in vitro. Upon p53 induction, a reporter construct containing the antiapoptotic gene survivin promoter, which contains a natural p53 binding site, was methylated in WT HCT116 cells but not in DNMT1 null or p53 null cells. Endogenous survivin gene repression involves cooperation between DNMT1 and p53 and is relieved by introduction of DNMT1-or p53-specific small inhibitory RNA. DNMT1 null cells did not exhibit a significant repressive effect for p53 responsive survivin and cdc25C gene expression compared with the parental cells. Normal human fibroblasts also exhibited similar DNMT1-and p53-mediated methylation of the survivin promoter, suggesting cooperation between p53 and DNMT1 in gene silencing.doxorubicin ͉ survivin ͉ small inhibitory RNA

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Section: Discussionmentioning

confidence: 99%

Human maintenance DNA (cytosine-5)-methyltransferase and p53 modulate expression of p53-repressed promoters

Estève

Chin²,

Pradhan³

2005

Proc. Natl. Acad. Sci. U.S.A.

149

127

View full text Add to dashboard Cite

show abstract

“…There is experimental evidence to suggest that p53 may regulate the methylation status and amplification of the EpCAM gene (8). However, recent analyses of primary breast cancer specimens demonstrate no significant correlation between promoter methylation and EpCAM expression, suggesting that alternate mechanisms may be involved in the regulation of EpCAM expression (9).…”

Section: Introductionmentioning

confidence: 99%

Transcriptional Repression of Epithelial Cell Adhesion Molecule Contributes to p53 Control of Breast Cancer Invasion

et al. 2009

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p53 is a tumor suppressor gene with well-characterized roles in cell cycle regulation, apoptosis and the maintenance of genome stability. Recent evidence suggests that p53 may also contribute to the regulation of migration and invasion. Epithelial cell adhesion molecule (EpCAM) is a transmembrane glycoprotein that is overexpressed in the majority of human epithelial carcinomas, including breast and colorectal carcinomas. We demonstrate by chromatin immunoprecipitation assays that p53 interacts with a candidate p53 binding site within the EpCAM gene. p53-mediated transcriptional repression of EpCAM was confirmed in gain-of-function, and loss-of-function experimental systems. Induction of wildtype p53 was associated with a significant dose-dependent decrease in EpCAM expression; conversely, specific ablation of p53 was associated with a significant increase in EpCAM expression. At the functional level, specific ablation of p53 expression is associated with increased breast cancer invasion, and this effect is abrogated by concomitant specific ablation of EpCAM expression. Taken together, these biochemical and functional data are the first demonstration that (1) wildtype p53 protein binds to a response element within the EpCAM gene and negatively regulates EpCAM expression, and (2) transcriptional repression of EpCAM contributes to p53 control of breast cancer invasion.

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“…Clinical and pathologic status, tumor histotype, histologic grade, levels of expression of estrogen receptor a and progesterone receptor (PGR), and fraction of proliferating cells (% Ki-67) were recorded (25). Tumor samples were analyzed for correlated expression of Trop-2, AKT, and TP53 (26,27) …”

Section: Tumor Patient Case Seriesmentioning

confidence: 99%

Trop-2 Induces Tumor Growth Through AKT and Determines Sensitivity to AKT Inhibitors

Guerra

Trerotola

Tripaldi

et al. 2016

Clinical Cancer Research

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Purpose: Inhibition of AKT is a key target area for personalized cancer medicine. However, predictive markers of response to AKT inhibitors are lacking. Correspondingly, the AKT-dependent chain of command for tumor growth, which will mediate AKTdependent therapeutic responses, remains unclear.Experimental Design: Proteomic profiling was utilized to identify nodal hubs of the Trop-2 cancer growth-driving network. Kinase-specific inhibitors were used to dissect Trop-2-dependent from Trop-2-independent pathways. In vitro assays, in vivo preclinical models, and case series of primary human breast cancers were utilized to define the mechanisms of Trop-2-driven growth and the mode of action of Trop-2-predicted AKT inhibitors.Results: Trop-2 and AKT expression was shown to be tightly coordinated in human breast cancers, with virtual overlap with AKT activation profiles at T308 and S473, consistent with functional interaction in vivo. AKT allosteric inhibitors were shown to only block the growth of Trop-2-expressing tumor cells, both in vitro and in preclinical models, being ineffective on Trop-2-null cells. Consistently, AKTtargeted siRNA only impacted on Trop-2-expressing cells. Lentiviral downregulation of endogenous Trop-2 abolished tumor response to AKT blockade, indicating Trop-2 as a mandatory activator of AKT.Conclusions: Our findings indicate that the expression of Trop-2 is a stringent predictor of tumor response to AKT inhibitors. They also support the identification of target-activatory pathways, as efficient predictors of response in precision cancer therapy. Clin Cancer Res; 22(16); 4197-205. Ó2016 AACR.

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Mutations of TP53 induce loss of DNA methylation and amplification of the TROP1 gene

Cited by 36 publications

References 40 publications

Human maintenance DNA (cytosine-5)-methyltransferase and p53 modulate expression of p53-repressed promoters

Human maintenance DNA (cytosine-5)-methyltransferase and p53 modulate expression of p53-repressed promoters

Transcriptional Repression of Epithelial Cell Adhesion Molecule Contributes to p53 Control of Breast Cancer Invasion

Trop-2 Induces Tumor Growth Through AKT and Determines Sensitivity to AKT Inhibitors

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