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5-Fluorouridine restores functional full-length p53 in TP53 nonsense mutant human tumor cells (Ribo-Seq)

ABSTRACT: The tumor suppressor gene TP53 is mutated in approximately half of all human tumors. Of those, around 10% are nonsense mutations that produce truncated and inactive p53 protein. Induction of translational readthrough is a promising approach for rescuing full-length p53 and thereby eliminate tumor cells with nonsense mutant TP53. To find novel nonsense mutant TP53 readthrough-inducing compounds with a tolerable toxicity profile, we performed an in silico screening of data at the National Cancer Institute database and identified 5-Fluorouracil (5-FU). We show here that 5-FU induces full-length p53 in human tumor cells carrying R213X nonsense mutant TP53 and that this activity is mediated by its metabolite 5-Fluorouridine (FUr). Ribo-seq analysis validated induction of translational readthrough by FUr. We also show that FUr is incorporated into RNA where it potentially allows base pairing of Arg tRNA at the R213X UGA premature termination codon. Full-length p53 rescued by FUr is transcriptionally active and triggers p53-dependent cell death. Moreover, treatment with 5-FU or FUr restores full-length p53 expression in TP53 R213X mutant human tumor xenografts in vivo. Our results suggest that induction of readthrough by 5-FU/FUr could contribute to therapeutic efficacy in patients with TP53 nonsense mutant tumors.

ORGANISM(S): Homo sapiens

PROVIDER: GSE196709 | GEO | 2022/12/01

REPOSITORIES: GEO

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5-Fluorouridine restores functional full-length p53 in TP53 nonsense mutant human tumor cells (RNA-Seq)

Project description:The tumor suppressor gene TP53 is mutated in approximately half of all human tumors. Of those, around 10% are nonsense mutations that produce truncated and inactive p53 protein. Induction of translational readthrough is a promising approach for rescuing full-length p53 and thereby eliminate tumor cells with nonsense mutant TP53. To find novel nonsense mutant TP53 readthrough-inducing compounds with a tolerable toxicity profile, we performed an in silico screening of data at the National Cancer Institute database and identified 5-Fluorouracil (5-FU). We show here that 5-FU induces full-length p53 in human tumor cells carrying R213X nonsense mutant TP53 and that this activity is mediated by its metabolite 5-Fluorouridine (FUr). Ribo-seq analysis validated induction of translational readthrough by FUr. We also show that FUr is incorporated into RNA where it potentially allows base pairing of Arg tRNA at the R213X UGA premature termination codon. Full-length p53 rescued by FUr is transcriptionally active and triggers p53-dependent cell death. Moreover, treatment with 5-FU or FUr restores full-length p53 expression in TP53 R213X mutant human tumor xenografts in vivo. Our results suggest that induction of readthrough by 5-FU/FUr could contribute to therapeutic efficacy in patients with TP53 nonsense mutant tumors.

2022-12-01 | GSE196710 | GEO

5-Fluorouridine restores functional full-length p53 in TP53 nonsense mutant human tumor cells

Project description:5-Fluorouridine restores functional full-length p53 in TP53 nonsense mutant human tumor cells

| PRJNA806945 | ENA

5-Fluorouridine restores functional full-length p53 in TP53 nonsense mutant human tumor cells (RNA-Seq)

Project description:5-Fluorouridine restores functional full-length p53 in TP53 nonsense mutant human tumor cells (RNA-Seq)

| PRJNA806948 | ENA

5-Fluorouridine restores functional full-length p53 in TP53 nonsense mutant human tumor cells (Ribo-Seq)

Project description:5-Fluorouridine restores functional full-length p53 in TP53 nonsense mutant human tumor cells (Ribo-Seq)

| PRJNA806946 | ENA

p53 influences 5-FU-induced chromatin accessibility [ChIP-seq]

Project description:5-Fluorouracil (5-FU) is one of the most common drugs used in chemotherapy because of its efficacy and stability. However, 5-FU has been known to work on only 10~15% of colon cancer patients. Therefore, the study of 5-FU sensitivity study is necessary to increase the survival of colon cancer patients. p53 is one of the factors that effect on drug sensitivity. Main function of p53 has been focused on transcription activity in cell death. Numerous drug related studies show that expression of wild-type p53 increases drug sensitivity in various cancer types through inducing apoptotic signaling pathways. Currently, it has been reported that p53 has both transcriptional and non-transcriptional activities in apoptosis. However, most studies about p53 non-transcriptional activities in apoptosis are mainly focused on p53 induced mitochondrial outer membrane permeabilization, triggering the release of pro-apoptotic factors. The chromatin structure and organization have strongly attracted because of their impacts in cellular phenotypes. Recent studies have been shown that changes in chromatin accessibility affect cell phenotypes for external stimuli. Since p53 plays an important role in drug sensitivity and 5-FU is an external stimulus for cancer cells, we hypothesized that p53 may effect on 5-FU sensitivity through different regulation of chromatin accessible regions between TP53-WT and TP53-KO cells. To determine the effect of p53 on chromatin accessibility modification associated with 5-FU sensitivity, ATAC-seq and RNA-seq were performed under 5-FU treatment on TP53-WT as drug sensitive and TP53-KO as drug resistant HCT116 cells. In this study, we found that 5-FU induces chromatin accessibility in both TP53-WT and TP53-KO cells. Moreover, our results show that 5-FU induced chromatin accessibility increases expression of apoptotic genes in TP53-WT HCT116 cells through p53 non-transcriptional activity in nucleus.

2021-02-10 | GSE157950 | GEO

p53 influences 5-FU-induced chromatin accessibility [ATAC-seq]

2021-02-10 | GSE157949 | GEO

Gene expression analysis of U251 human glioblastoma cell line

2012-12-10 | GSE35454 | GEO

Gene expression analysis of U251 human glioblastoma cell line

Project description:The human TP53 gene is frequently mutated in tumors and cell lines. Unlike other tumor suppressors that are commonly inactivated by deletions or nonsense mutations, the majority of p53-mutations are missense point mutations that result in the expression of a full-length protein with an altered amino acid that has lost sequence specific DNA-binding. Expression of mutant p53 (mutp53) confers advantages to tumor cells and transcriptional regulation of several genes mediating the beneficial effects has been shown to play a role. However, molecular mechanisms of transcriptional regulation by mutp53 are still poorly understood. We used the glioblastoma-derived U-251 MG human cell line endogenously expressing mutp53 protein (R273H mutation) to analyze gene expression profiles on Agilent Whole Human Genome Microarray after transient and stable depletion of mutp53 expression. Gene expression data was correlated with a ChIP study on a custom tiling array to understand the contribution of endogenously expressed mutp53 to transcriptional regulation. This series of microarray experiments contains the gene expression profiles of glioblastoma-derived U-251 MG human cell lines engineered to constitutively express a p53-specific shRNA or scrambled control shRNA. To reverse the effect of mutp53 depletion, stable clones were modified by stable integration of a mutp53-R273H expression construct or empty pCDNA3 vector as a control. In addition, we performed gene expression analysis of U-251 MG cells transiently transfected with p53-specific siRNA or control siRNA (3 biological replicates each).

2012-12-10 | E-GEOD-35454 | biostudies-arrayexpress

Mutant p53 interactome study with IP-MS

Project description:Inactivating TP53 mutations lead to a loss of function of p53, but can also often result in oncogenic gain-of-function (GOF) of mutant p53 (mutp53) proteins which promote tumor development and progression. The GOF activities of TP53 mutations are well documented, but the mechanisms involved remain poorly understood. Here, we study the mutp53 interactome with IP-MS.

2023-11-27 | PXD047094 | Pride

Mis-splicing Drives Loss of Function of p53E224D Point Mutation

Project description:Background: Tp53 is the most commonly mutated gene in cancer. Canonical Tp53 DNA damage response pathways are well characterized and classically thought to underlie the tumor suppressive effect of Tp53. Challenging this dogma, mouse models have revealed that p53 driven apoptosis and cell cycle arrest are dispensable for tumor suppression. Here, we investigated the inverse context of a p53 mutation predicted to drive expression of canonical targets, but is detected in human cancer. Methods: We established a novel mouse model with a single base pair mutation (GAG>GAC, p53E221D) in the DNA-Binding domain that has wild-type function in screening assays, but is paradoxically found in human cancer in Li Fraumeni syndrome. Using mouse p53 E221D and the the analogous human p53E224D mutant, we evaluated expression, transcriptional activation, and tumor suppression in vitro and in vivo. Results: Expression of human p53E224D from cDNA translated to a fully functional p53 protein. However, p53 E221D/E221D RNA transcribed from the endogenous locus is mis-spliced resulting in nonsense mediated decay. Moreover, fibroblasts derived from p53 E221D/E221D mice do not express a detectable protein product. Mice homozygous for p53 E221D exhibited increased tumor penetrance and decreased life expectancy compared to p53 WT animals. Conclusions: Mouse p53 E221D and human p53 E224D mutations lead to splice variation and a biologically relevant p53 loss of function in vitro and in vivo.

2024-07-28 | GSE239745 | GEO

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