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Expression profiling of MCF7 cells upon nutlin3a treatment

ABSTRACT: The tumor suppressor p53 can induce various biological responses. Yet it is not clear whether it is p53 in vivo promoter selectivity that triggers different transcription programs leading to different outcomes. Our analysis of genome-wide chromatin occupancy by p53 using ChIP-seq (deposited in Sequence Read Archive database as SRP007261) revealed “p53 default program”, i.e. the pattern of major p53-bound sites that is similar upon p53 activation by nutlin3a, RITA or 5-FU in breast cancer cells, despite different biological outcomes triggered by these compounds. Parallel analysis of gene expression allowed identification of 280 previously unknown p53 target genes, including p53-repressed AURKA. The consensus p53 binding motif was present more frequently in p53-induced, than in repressed targets, indicating different mechanisms of gene activation versus repression. We identified several possible cofactors of p53, and found that STAT3 antagonised p53-mediated repression of a subset of genes, including AURKA. Finally, we showed that the expression of the novel p53 targets correlates with p53 status and survival in breast cancer patients. We used microarrays to detail the global programme of gene expression changed upon nutlin3a treatment and knocking-down of STAT3 transcription program

ORGANISM(S): Homo sapiens

PROVIDER: GSE30183 | GEO | 2012/09/07

SECONDARY ACCESSION(S): PRJNA143965

REPOSITORIES: GEO

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Expression profiling of MCF7 cells upon nutlin3a treatment

Project description:The tumor suppressor p53 can induce various biological responses. Yet it is not clear whether it is p53 in vivo promoter selectivity that triggers different transcription programs leading to different outcomes. Our analysis of genome-wide chromatin occupancy by p53 using ChIP-seq (deposited in Sequence Read Archive database as SRP007261) revealed “p53 default program”, i.e. the pattern of major p53-bound sites that is similar upon p53 activation by nutlin3a, RITA or 5-FU in breast cancer cells, despite different biological outcomes triggered by these compounds. Parallel analysis of gene expression allowed identification of 280 previously unknown p53 target genes, including p53-repressed AURKA. The consensus p53 binding motif was present more frequently in p53-induced, than in repressed targets, indicating different mechanisms of gene activation versus repression. We identified several possible cofactors of p53, and found that STAT3 antagonised p53-mediated repression of a subset of genes, including AURKA. Finally, we showed that the expression of the novel p53 targets correlates with p53 status and survival in breast cancer patients. We used microarrays to detail the global programme of gene expression changed upon nutlin3a treatment and knocking-down of STAT3 transcription program MCF7 cell with or without knock-down of STAT3 were treated with nutlin3a and collected for RNA extraction and hybridization on Affymetrix microarrays.

2012-09-07 | E-GEOD-30183 | biostudies-arrayexpress

Effect of wtp53-reactivating drug RITA on HCT116 cells

Project description:Since its discovery as a tumour suppressor some fifteen years ago, the transcription factor p53 has attracted paramount attention for its role as “the guardian of the genome”. TP53 mutations occur so frequently in cancer, regardless of patient age or tumour type, that they appear to be part of the life history of at least 50% of human tumours. In most tumours that retain wild-type p53, its function is inactivated due to deregulated HDM2, a protein which binds to p53 and which can inhibit the transcriptional activity of p53 and induce its degradation. RITA is a low-molecular-weight compound which addresses the second group of tumours retaining functionally reactive wt p53. It was found in a screening of the National Cancer Institute (NCI) library of low-molecular-weight compounds based on its ability to selectively kill wtp53-containing cells. RITA binds directly to p53 and diplaces its main destructor Mdm2, as well as inducing a shift in the conformation of p53. This is in contrast to the wtp53-reactivating compound Nutlin3a, which targets Mdm2, inhibiting its ability to degrade p53. Using microarray technology we have explored the effect of RITA on the transcriptome of isogenic cell-lines with knocked-out (KO) or intact (WT) TP53. While the effects on KO cells are below detection limit, the effects on WT cells are profound. The known p53 targets induced are predominately apoptotic, in contrast to the genes affected by Nutlin3a, which are exclusively growth-arrest genes. Keywords: Antitumor agent HCT116 parental and HCT116 p53-null (HCT116 TP53-/-) cells were subjected to treatment with 1uM RITA for 12h, or left untreated. The experiment was done in three independent biological replicates.

2009-02-28 | E-GEOD-11578 | biostudies-arrayexpress

Gene expression profiling of human neural crest cells and smooth muscle cells treated with DMSO or Nutlin3a

Project description:Activation of the p53 transcription factor triggers apoptosis only in certain cell types. Human neural crest cells (hNCCs), which can be generated from human embryonic stem cells, undergo apoptosis when treated with the p53 activating drug Nutlin3a. In contrast, when hNCCs are differentiated towards the smooth muscle cell lineage (early-hSMCS), they no longer undergo apoptosis in response to Nutlin3a treatment. Here, we sought to determine whether the transcriptional response to p53 activation differs between cells that are susceptible to p53-driven apoptosis and cells that are resistant to p53-driven apoptosis. To this end, we performed RNA-seq to assess the transcriptional response to Nutlin3a treatment in hNCCs and early-hSMCs.

2019-07-04 | GSE128191 | GEO

RNA_seq and Ribo_seq analyses of control and Nutlin3a-treated MCF7 cells (20 hrs)

Project description:We used RNA-seq and Ribo-seq analyses to examine the effect of Nutlin3a (activator of p53) treatment of translation efficiency (TE)

2017-06-13 | GSE96714 | GEO

Effect of wtp53-reactivating drug RITA on HCT116 cells

2009-02-28 | GSE11578 | GEO

Transcription profiling of human MCF7 time-series upon RITA treatment.

Project description:Targeting “oncogene addiction” is a promising strategy for anti-cancer therapy. Here, we report a potent inhibition of crucial oncogenes by p53 upon reactivation with small molecule RITA in vitro and in vivo. RITA-activated p53 unleashes transcriptional repression of anti-apoptotic proteins Mcl-1, Bcl-2, MAP4, and survivin, blocks Akt pathway on several levels and downregulates c-Myc, cyclin E and B-catenin. p53 ablates c-Myc expression via several mechanisms at transcriptional and posttranscriptional level. We show that transrepression of oncogenes correlated with higher level of p53 bound to chromatin-bound p53 than transactivation of pro-apoptotic targets. Inhibition of oncogenes by p53 reduces the cell’s ability to buffer pro-apoptotic signals and elicits robust apoptosis. Our study highlights the role of transcriptional repression for p53-mediated tumor suppression. Experiment Overall Design: Breast carcinoma cell-line MCF7 was treated with the small-molecule p53 activator RITA for 2h, 8h, 16h and 24h.

2009-05-15 | E-GEOD-13291 | biostudies-arrayexpress

Bulk RNA-seq of Quiescent and Nutlin3a-Induced Senescent mouse pulmonary fibroblasts

Project description:Purpose: Use RNA-seq strategy to characterize the differentially expressed genes and significant transposable elements in quiescent and nutlin3a-induced senescent pulmonary fibroblasts to identify the factors and possible neoantigens in activating the cytotoxic T cell immunity. Methods: FACSorted primary pulmonary fibroblasts were utilized for the preparation of bulk RNA-seq libraries. Quiescence was induced by starvation and senescence was induced by nutlin 3a treatment.

2022-08-27 | GSE198397 | GEO

MCF7 time-series upon RITA treatment.

2009-05-12 | GSE13291 | GEO

Illumina RNA-seq of Human rhabdomyosarcoma Rh36 cell mouse xenograft tumors: effect of RITA, GANT61 and RITA/GANT61 combination treatments on xenograft tumor growth

Project description:Overactivation of the Hedgehog (HH) signaling pathway is implicated in many cancers. In this study, we demonstrate that the small molecule RITA, a p53 activator, effectively downregulates HH signaling in human medulloblastoma and rhabdomyosarcoma cells irrespective of p53. This is mediated by a ROS-independent activation of the MAP kinase JNK. We also show that in vitro RITA sensitized cells to the GLI antagonist GANT61, as co-administration of the two drugs had more pronounced effects on cell proliferation and apoptosis. In vivo administration of RITA or GANT61 suppressed rhabdomyosarcoma xenograft growth in nude mice; however, co-administration did not further enhance tumor suppression, even though cell proliferation was decreased. RITA was more potent than GANT61 in downregulating HH target gene expression; surprisingly, this suppressive effect was almost completely eliminated when the two drugs were administered together. Notably, RNA-seq demonstrated a broader response of pathways involved in cancer cell growth in the combination treatment, providing a plausible interpretation for tumor reduction in the absence of HH signaling downregulation.

2020-11-12 | GSE161235 | GEO

GD3 Synthase Is a Master Regulator of Wild-Type p53–Mediated Apoptosis and Mutant p53–Mediated Tumorigenesis

Project description:We noted that the increased expression of GD3S enables breast cancer cells to evade cell death induced by the stabilization of p53 through Nutlin3A treatment, and we aim to explore the molecular mechanisms underlying these observed effects.

2023-12-02 | GSE248670 | GEO

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