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Long non-coding RNA TILR constitutively represses TP53 and apoptosis induction in lung cancer II

ABSTRACT: Recent evidence suggests that non-coding RNAs play an integral regulatory role in numerous functions in lung cancer development. Here, we report identification of a novel lncRNA, herein termed TP53-inhibiting lncRNA (TILR), which plays a role as a constitutive negative regulator of p53 expression and hence its functions including activation of downstream genes such as p21 and MDM2 and induction of apoptosis. Proteomic search for TILR-associated protein revealed the association with PCBP2, and the mid-portion of TILR was required for both PCBP2 and p53 mRNA binding. In addition, depletion of PCBP2 faithfully phenocopied effects of TILR silencing. We also found that TILR suppressed p53 expression post-transcriptionally as well as via a positive feedback loop between p53 and the Fanconi anemia pathway genes. Taken together, our findings clearly demonstrate that TILR constitutively inhibits p53 expression in cooperation with PCBP2, maintaining p53 transcriptional activity at a level sufficiently low for avoidance of spurious apoptosis induction.

ORGANISM(S): Homo sapiens

PROVIDER: GSE180944 | GEO | 2022/12/19

REPOSITORIES: GEO

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Long non-coding RNA TILR constitutively represses TP53 and apoptosis induction in lung cancer

Project description:Recent evidence suggests that non-coding RNAs play an integral regulatory role in numerous functions in lung cancer development. Here, we report identification of a novel lncRNA, herein termed TP53-inhibiting lncRNA (TILR), which plays a role as a constitutive negative regulator of p53 expression and hence its functions including activation of downstream genes such as p21 and MDM2 and induction of apoptosis. Proteomic search for TILR-associated protein revealed the association with PCBP2, and the mid-portion of TILR was required for both PCBP2 and p53 mRNA binding. In addition, depletion of PCBP2 faithfully phenocopied effects of TILR silencing. We also found that TILR suppressed p53 expression post-transcriptionally as well as via a positive feedback loop between p53 and the Fanconi anemia pathway genes. Taken together, our findings clearly demonstrate that TILR constitutively inhibits p53 expression in cooperation with PCBP2, maintaining p53 transcriptional activity at a level sufficiently low for avoidance of spurious apoptosis induction.

2022-12-19 | GSE180940 | GEO

p53-induced apoptosis is specified by a translation program regulated by PCBP2 and DHX30.

Project description:Activation of p53 by the small molecule Nutlin can result in a combination of cell cycle arrest and apoptosis. The relative strength of these events is difficult to predict, leaving uncertainty as to the therapeutic benefits of Nutlin. Here, we report a new translation control mechanism shaping p53-dependent apoptosis. We performed polysomal profiling in the cell lines SJSA1 and HCT116, of which only the first undergoes robust cell death in response to p53 activation by Nutlin. We establish Nutlin-induced apoptosis in SJSA1 cells to be associated with a set of translationally enhanced mRNAs carrying a newly identified 3’UTR motif which we labeled CG-motif. We identified PCBP2 and DHX30 as interactor proteins of the CG-motif that are more abundant in HCT116 cells compared to SJSA1. The binding of DHX30 to the CG-motif detected in HCT116 cells was shown to be dependent on PCBP2. Interestingly, DHX30 depletion enhances polysome association of CG-motif mRNAs in HCT116 cells, shifting their outcome towards apoptosis. In U2OS, an osteosarcoma-derived cell line that unlike SJSA1 undergoes persistent cell cycle arrest in response to Nutlin, DHX30 is highly expressed and its depletion enhances the expression of CG-motif mRNAs.

2020-03-30 | GSE95024 | GEO

Homo sapiens

Project description:p53-induced apoptosis is specified by a translation program regulated by PCBP2 and DHX30.

| PRJNA375753 | ENA

SPARCLE, a p53-induced lncRNA, controls apoptosis after genotoxic stress by promoting PARP-1 cleavage

Project description:p53, master transcriptional regulator of the genotoxic stress response, controls cell cycle arrest and apoptosis following DNA damage. Here we identify a p53-induced lncRNA SPARCLE (Suicidal PARP-1 Cleavage Enhancer) adjacent to miR-34b/c required for p53-mediated apoptosis. SPARCLE is a ~770 nucleotide, nuclear lncRNA induced one day after DNA damage. Despite low expression (<15 copies/cell), SPARCLE deletion increases DNA repair and reduces DNA damage-induced apoptosis as much as p53 deficiency, while its over-expression restores apoptosis in p53-deficient cells. SPARCLE does not alter gene expression. SPARCLE causes apoptosis by acting as a caspase-3 cofactor for PARP-1 cleavage, which separates its N-terminal (NT) DNA binding domain from PARP-1 catalytic domains. NT-PARP-1 binds to DNA breaks but, lacking its PARylation domains, does not initiate DNA repair. In fact, expressing NT-PARP-1 in SPARCLE-deficient cells increases unrepaired DNA damage and restores apoptosis after DNA damage. Thus, as a PARP-1 cleavage cofactor, SPARCLE enhances p53-induced apoptosis.

2022-02-01 | GSE144510 | GEO

p53 independent TAF6delta target genes.

Project description:To elucidate the impact of TAF6d on cell death and gene expression, here we have employed modified antisense oligonucleotides to enforce expression of endogenous TAF6d. The induction of endogenous TAF6d triggered apoptosis in tumor cell lines, including cells devoid of p53. Microarray experiments revealed that TAF6d activates gene expression independently of cellular p53 status. Our data define TAF6d as a pivotal node in a signaling pathway that acts immediately downstream of p53 to control gene expression programmes and apoptosis. Keywords: Treatment with splice site switching antisense oligonucleotides, induction of apoptosis Biological triplicates, 4 conditions: isogenic p53+/+ and -/- cells; control oligonucleotide, TAF6 AS2 oligonucleotide

2008-06-26 | E-GEOD-10795 | biostudies-arrayexpress

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

Transcription profiling by array of Fanconi Anemia patient (FANCA) EBV cell line transduced with control shRNA or a shRNA targeting p53 and treated with a Mitomycin C (MMC) pulse

Project description:Time point (H0, H24, H72) expression data from an EBV cell line obtained from a Fanconi Anemia patient (FANCA) transduced with a control shRNA (sh Ctrl) (n=3) or a shRNA targeting p53 (sh p53) (n=3) and treated with a brief MMC pulse.

2012-10-23 | E-MTAB-1099 | biostudies-arrayexpress

p53 activates the long noncoding RNA Pvt1b to inhibit Myc and suppress tumorigenesis

Project description:P53 activation in response to cellular stress has long been known to result in downregulation of c-myc, a gene that is frequently overexpressed in cancer due to its role in promoting cellular proliferation. However, the mechanism underlying this p53 dependent myc repression is poorly understood. Here we report p53 regulation of the lncRNA PVT1, a neighboring myc gene which is upregulated following p53 activation via p53 binding to a canonical p53 response element (p53RE) in the first intron of PVT1. Specifically, we find that p53 activation results in induction of an isoform of PVT1 initiated from an alternative first exon, which we have termed PVT1alt. When the PVT1 p53RE is mutated and PVT1alt induction is inhibited, we observe increased levels of myc mRNA in cells undergoing DNA damage or oncogenic stress and corresponding increases in cellular proliferation. The PVT1alt RNA is required for this p53-dependent myc repression, suggesting a important growth suppressive role for this lncRNA in the p53 response. Our study reveals a novel mode of myc regulation in cis by an alternative lncRNA isoform, providing insight into an important mechanism of crosstalk between the p53 and myc transcriptional networks.

2020-01-20 | GSE126940 | GEO

p53 independent TAF6delta target genes.

2008-06-26 | GSE10795 | GEO

aCGH analysis of Palb2GT/+;p53-/- and Palb2+/+;p53-/- lymphomas

Project description:Palb2 interacts with BRCA1 and BRCA2 in supercomplexes involved in DNA repair via homologous recombination. Heterozygous germline mutations in PALB2 confer a moderate risk of breast cancer while biallelic PALB2 mutations are linked to a severe form of Fanconi anaemia characterized by early childhood solid tumours and severe chromosomal instability. In contrast to BRCA1- or BRCA2-associated cancers, breast tumours in heterozygous PALB2 mutation carriers do not show loss of the wild type allele, suggesting PALB2 might be haploinsufficient for tumour suppression. To study the role of PALB2 in development and tumourigenesis, we have generated Palb2GT mouse mutants using a gene trap approach. Whereas Palb2GT/GT homozygous mutant embryos died at mid-gestation due to massive apoptosis, Palb2GT/+ heterozygous mice were viable and did not show any obvious abnormalities. Deletion of p53 alleviated the phenotype of Palb2GT/GT embryos, but did not rescue embryonic lethality. In addition, loss of p53 did not significantly collaborate with Palb2 heterozygosity in tumourigenesis in heterozygous or homozygous p53 knockout mice. Tumours arising in Palb2GT/+;p53+/– or Palb2GT/+;p53–/– compound mutant mice retained the wild type Palb2 allele and did not display increased genomic instability. Comparison of 15 Palb2GT/+;p53-/- and 11 Palb2+/+;p53-/- lymphomas. Spleen/liver DNA of the same animal was used as reference material.

2011-01-21 | E-GEOD-26723 | biostudies-arrayexpress

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