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Gene expression profiling after Wig-1 knockdown in HCT116 cancer cell line

ABSTRACT: Wig-1 is a p53 target gene that encodes an RNA-binding protein involved in regulation of mRNA stability through binding to AU-rich elements (AREs). The aims of this study were to identify novel Wig-1 target mRNAs and to characterize the mechanisms of their regulation. Using a microarray approach, we identified 2447 transcripts with >4-fold differential expression between Wig-1 siRNA and control siRNA treated HCT116 cells. Among the deregulated transcripts we found a number of p53 target genes. We demonstrated that Wig-1increases 14-3-3σ transcription while it binds to an ARE in the FAS 3’UTR and decreases the FAS mRNA stability. Furthermore, we show that Wig-1 depletion favours cell death rather that cell cycle arrest after DNA damage. We propose a role of Wig-1 in directing the p53 stress response towards cell cycle arrest rather than cell death through regulation of 14-3-3σ and FAS mRNA levels.

ORGANISM(S): Homo sapiens

PROVIDER: GSE43046 | GEO | 2014/03/01

SECONDARY ACCESSION(S): PRJNA184694

REPOSITORIES: GEO

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Gene expression profiling after Wig-1 knockdown in HCT116 cancer cell line

Project description:Wig-1 is a p53 target gene that encodes an RNA-binding protein involved in regulation of mRNA stability through binding to AU-rich elements (AREs). The aims of this study were to identify novel Wig-1 target mRNAs and to characterize the mechanisms of their regulation. Using a microarray approach, we identified 2447 transcripts with >4-fold differential expression between Wig-1 siRNA and control siRNA treated HCT116 cells. Among the deregulated transcripts we found a number of p53 target genes. We demonstrated that Wig-1increases 14-3-3M-OM-^C transcription while it binds to an ARE in the FAS 3M-bM-^@M-^YUTR and decreases the FAS mRNA stability. Furthermore, we show that Wig-1 depletion favours cell death rather that cell cycle arrest after DNA damage. We propose a role of Wig-1 in directing the p53 stress response towards cell cycle arrest rather than cell death through regulation of 14-3-3M-OM-^C and FAS mRNA levels. Use HEEBO microarrays to examine the effects of Wig-1 protein knockdown by siRNA silencing in HCT116 cells. 3 microarrays in total.

2014-03-01 | E-GEOD-43046 | biostudies-arrayexpress

Gene expression patterns induced by 5-Fluorouracil in breast cancer cell lines

Project description:We have compared the changes in cell cycle and cell death parameters induced by 2 different concentrations of 5-FU (IC50 and IC80) in the breast adenocarcinoma cell line MCF7. G1/S cell cycle arrest was associated with both concentrations, whereas cell death was mainly induced after IC80 5-FU. These changes were correlated with gene expression assessed by cDNA microarray analysis. Main findings included an overexpression of p53 target genes involved in cell cycle and apoptosis (CDKN1A/p21, TP53INP, TNFRSF6/FAS and BBC3/PUMA), and significant repression of Myc. High dose 5-FU also induced a higher regulation of the mitochondrial death genes APAF1, BAK1 and BCL2, and induction of genes of the ID family. Time and dose-dependent changes in gene expression, induced by 5-Fluorouracil, in breast carcinoma cell lines MCF7, and MDA-MB-435.

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Gene expression patterns induced by 5-Fluorouracil in breast cancer cell lines

2006-04-07 | GSE2584 | GEO

AMBRA1 controls the translation of immune-specific genes in T lymphocytes

Project description:T cell receptor (TCR) engagement causes a global cellular response that entrains signaling pathways, cell cycle regulation, and cell death. The molecular regulation of mRNA translation in these processes is poorly understood. During a whole-genome CRISPR screen for regulators of CD95 (Fas/APO-1)-mediated T cell death, we identified AMBRA1, a protein previously studied for its roles in autophagy, E3 ubiquitin ligase activity, and cyclin regulation. T cells lacking AMBRA1 resist Fas-mediated cell death by down-regulating FAS expression at the translational level. We show that AMBRA1 is a vital regulator of ribosome protein biosynthesis and loading on select mRNAs that plays a key role in balancing TCR signaling with cell cycle regulation pathways. We also found that AMBRA1 itself is translational controlled by TCR stimulation via the CD28-PI3K-mTORC1-EIF4F pathway. Together, these findings shed light on the molecular control of translation after T cell activation and implicate AMBRA1 as a translational regulator that governs TCR signaling, cell cycle progression and T cell death.

2024-10-08 | MSV000096042 | MassIVE

Gene expression data from hCdc73 knock-down HEK293 cells under confluent and sparse condition.

Project description:The parafibromin/hCdc73 is a component of the PAFc, which controls RNA polymerase II-mediated general transcription. In parathyroid carcinoma and familial autosomal dominant hyperparathyroidism-jaw tumor (HPT-JT), hCdc73 mutations are heavily implicated, yet the underlying mechanism of its carcinogenic action is poorly understood. Here, we demonstrate that hCdc73 specifically controls mRNA stability of p53, and p53-mediated apoptosis. hCdc73 is associated with mature p53 mRNA in the cytoplasm and facilitates its degradation. Cytoplasmic hCdc73 physically interacts with eEF1Bγ and hSki8, and this interaction is required to bind and destabilize p53 mRNA. Furthermore, enhanced association of p53 mRNA with a cancer driven hCdc73(K34Q) mutant was also observed. As a result, reduced p53 expression as well as enhanced cell proliferation was acquired in the hCdc73 (K34Q) overexpressed cells. Altogether, our findings indicate that hCdc73 directly targets p53 mRNA to repress p53 expression, and aberrant regulation of this interaction may lead to tumor progression. Total RNA was obtained from control siRNA or hCdc73 siRNA transfected cells, under sparse or confluent cell density condition.

2014-09-23 | E-GEOD-61601 | biostudies-arrayexpress

Regulation of P53 signaling in breast cancer by the E3 ubiquitin ligase RNF187

Project description:The tumor suppressor P53 plays critical roles in prohibiting cancer. P53 is rarely mutated and still functional in luminal types of breast cancer. According to current knowledge, wild type P53 function is tightly controlled by post-translational modification, such as ubiquitination. Several ubiquitin ligases were shown to regulate P53 ubiquitination and protein stability. Here, we report RNF187, a RING family ubiquitin ligase, facilitates breast cancer growth and inhibits apoptosis via modulating P53 signaling. RNF187 is elevated in breast cancer and correlates with breast cancer survival only in P53 wild type groups. The bio-informatics analysis shows that RNF187 negatively correlates P53 target gene expression, such as IGFBP3 and FAS in breast cancer. RNF187 depletion inhibits breast cancer growth and facilitates cell death. RNA sequencing analysis indicates that RNF187 could be an important modifier for P53 signaling. Further experiments show that RNF187 interacts with P53 and promotes P53 degradation via facilitating P53 poly-ubiquitination in breast cancer cells. Interesting, the in vitro ubiquitin assay shows that RNF187 could directly ubiquitinate P53, which is independent of MDM2. These finding reveals a novel direct P53 regulator and a potential therapeutic target for breast cancer.

2021-09-01 | GSE183008 | GEO

LncRNA LIMp27 regulates the DNA damage response through p27 in p53-defective cancer cells

Project description:P53 inactivation occurs in about 50% of human cancers, where p53-driven p21 activity is devoid and p27 becomes essential for the establishment of the G1/S checkpoint upon DNA damage. Here, we show that the E2F1-responsive lncRNA LIMp27 selectively represses p27 expression and contributes to proliferation, tumorigenicity, and treatment resistance in p53-defective colon adenocarcinoma (COAD) cells. LIMp27 competes with p27 mRNA for binding to cytoplasmically localized hnRNA0, which otherwise stabilizes p27 mRNA leading to cell cycle arrest at the G0/G1 phase. In response to DNA damage, LIMp27 is upregulated in both wild-type and p53-mutant COAD cells, whereas cytoplasmic hnRNPA0 is only increased in p53-mutant COAD cells due to translocation from the nucleus. Moreover, high LIMp27 expression is associated with poor survival of p53-mutant but not wild-type p53 COAD patients. These results uncover a lncRNA mechanism that promotes p53-defective cancer pathogenesis and suggest that LIMp27 may constitute a target for the treatment of such cancers.

| MSV000090292 | MassIVE

Targeting USP2 regulation of VPRBP-mediated degradation of p53 and PD-L1 for cancer therapy

Project description:Here, we identify the USP2 (ubiquitin specific peptidase 2)-VPRBP (viral protein R binding protein) axis as a new pathway for p53 regulation. Like Mdm2 (Mouse double minute 2), VPRBP is a potent repressor of p53 but VPRBP stability is controlled by USP2. Interestingly, the USP2-VPRBP axis is also involved in PD-L1 (programmed death-ligand 1) regulation. Strikingly, in immunocompetent mouse models, the combination of a small-molecule USP2 inhibitor and anti-PD1 monoclonal antibody leads to complete regression of the tumors expressing wild-type p53. In contrast to Mdm2, knockout of the USP2 gene in mice has no obvious effect in normal tissues. Moreover, no obvious toxicity is observed upon the USP2 inhibitor treatment in vivo as Mdm2-mediated regulation of p53 remains intact. These data demonstrate that USP2 is a promising target to induce potent tumor suppression without obvious toxicity. Our study reveals a new strategy for p53-based therapy by circumventing the toxicity issue.

2023-03-15 | PXD040477 | Pride

Targeting USP2 regulation of VPRBP-mediated degradation of p53 and PD-L1 for cancer therapy

2023-03-15 | PXD040473 | Pride

Fas promotes T helper-17 cell differentiation and inhibits development of T helper-1 cells by binding and sequestering the STAT1 transcription factor

Project description:The death receptor Fas removes activated lymphocytes through apoptosis. Previous transcriptional profiling predicted that Fas positively regulates interleukin (IL)-17-producing T helper (Th17) cells. We here demonstrate that Fas promoted the generation and stability of Th17 cells and prevented their differentiation into Th1 cells. Mice with T cell- and Th17 cell-specific deletion of Fas were protected from induced autoimmunity and Th17 cell differentiation and stability was impaired. Fas deficient Th17 cells instead developed a Th1 cell-like transcriptional profile, which we predicted by a new algorithm to depend on STAT1. Experimentally, Fas indeed bound and sequestered STAT1 and Fas deficiency enhanced IL-6 induced STAT1 activation and nuclear translocation, whereas Fas-STAT1 double-deficiency reversed the transcriptional changes induced by Fas deficiency. Thus, our computational and experimental approach identified Fas as a regulator of the Th17-to-Th1 cell balance by controlling the availability of the opposing STAT1 and STAT3 proteins with direct impact on autoimmunity.

2018-03-10 | GSE111244 | GEO

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