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

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: GSE180940 | GEO | 2022/12/19

REPOSITORIES: GEO

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

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 | GSE180944 | GEO

Analysis of gene expression in p53-null cell types following deletion of Mdm2

Project description:RNA-sequencing was performed to gain insight into the mechanism responsible for the apoptosis and cell cycle arrest induced by loss of Mdm2 in p53-null cells. Following CreERT2-mediated deletion of Mdm2 in three p53-null cell types (T cell lymphoma, sarcoma, and fibroblasts), RNA-sequencing was performed. This high-throughput data revealed Mdm2 deletion in p53-null cells upregulated p53/p73 transcriptional target genes known to induce apoptosis and cell cycle arrest.

2017-09-06 | GSE98705 | GEO

Identification of the RNAs that bind with MDM2 by high-throughput RIP-seq in MDA-MB-231 and MCF-7 cells

Project description:The E3 ligase MDM2 promotes tumor growth and progression by inducing ubiquitin-mediated degradation of P53 and other tumor suppressing proteins. Here, we identified an MDM2-interacting lncRNA NRON, which promotes tumor formation by suppressing both P53-dependent and independent pathways. NRON binds to MDM2 and MDMX (MDM4) via two different stem-loops respectively and induces their heterogenous dimerization, thereby enhancing the E3 ligase activity of MDM2 towards its tumor suppressing substrates, including P53, RBI and NFATI, etc.

2023-06-19 | GSE226511 | GEO

A circular RNA from the MDM2 locus regulates proliferation by suppressing basal p53 levels

Project description:Circular RNAs (circRNAs) are a class of noncoding RNAs produced by a non-canonical form of alternative splicing called back-splicing. To investigate a potential role of circRNAs in the p53 pathway, we analyzed RNA-seq data from colorectal cancer cell lines (HCT116, RKO and SW48) in the presence or absence of DNA damage. Surprisingly, unlike the strong p53-dependent induction of hundreds of p53-induced mRNAs, only a few circRNAs were induced from the p53-induced genes. Circ-MDM2, an annotated circRNA from the MDM2 locus, was one of the handful of circRNAs that originated from a p53-induced gene. Given the central role of MDM2 in suppressing p53 protein levels and p53 activity, we investigated the function of circ-MDM2. Knocking down circ-MDM2 with siRNAs that targeted the circ-MDM2 junction and had no effect on linear MDM2 mRNA, resulted in increased basal p53 levels and growth defects in vitro and in vivo. Consistent with these results, transcriptome profiling showed increased expression of several direct p53 targets, reduced Rb phosphorylation and defects in G1-S progression upon silencing circ-MDM2. Our results reveal the role of a novel circRNA by which the MDM2 locus suppresses p53 levels and cell cycle progression.

2020-03-04 | GSE138016 | GEO

PPM1D suppresses p53-dependent transactivation and cell death by inhibiting the HRI-eIF2alpha-ATF4 pathway [RNA-seq]

Project description:The p53 transcription factor is a master regulator of cellular stress responses restrained by repressors such as MDM2 and the phosphatase PPM1D. Activation of p53 with pharmacological inhibitors of its repressors is being tested in clinical trials for cancer therapy, but efficacy has been limited by poor induction of tumor cell death. We demonstrate that dual inhibition of MDM2 and PPM1D induces cell death in multiple cancer cell types via amplification of the p53 transcriptional program through the eIF2alpha -ATF4 pathway. PPM1D inhibition induces phosphorylation of eIF2alpha, ATF4 accumulation, and ATF4-dependent enhancement of p53-dependent transactivation upon MDM2 inhibition. Dual inhibition of p53 repressors depletes heme and induces HRI-dependent eIF2alpha phosphorylation. Pharmacological induction of eIF2alpha phosphorylation synergizes with MDM2 inhibition to induce cell death and halt tumor growth in mice. These results demonstrate that PPM1D inhibits both the p53 network and the integrated stress response controlled by eIF2alpha, with clear therapeutic implications.

2022-11-01 | GSE191148 | GEO

PPM1D suppresses p53-dependent transactivation and cell death by inhibiting the HRI-eIF2alpha-ATF4 pathway [ChIP-seq]

2022-09-01 | GSE191149 | 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

CDK4 inhibition diminishes p53 activation by Mdm2-antagonists

Project description:CDK4 inhibitors have reached clinical approval for cancer therapy. In parallel, the p53 antagonist Mdm2 remains an attractive target for anti-cancer therapy, including numerous clinical studies. The genes encoding Mdm2 and CDK4 are frequently co-amplified in human malignancies, most notably in liposarcomas, suggesting their combined targeting for therapy. Here we show, however, that small compounds that inhibit Mdm2 and CDK4 antagonize each other rather than synergize in their cytotoxicity towards sarcoma cells. CDK4 inhibition attenuates the induction of p53-responsive genes upon Mdm2 inhibition, and similar results were obtained when depleting Mdm2 and/or CDK4 with siRNA. CDK4 inhibitors also interfered with p53 activity in response to DNA damage. CDK4 inhibition did not reduce p53 binding or histone acetylation to promoters, but rather attenuated the subsequent recruitment of RNA polymerase II. The complexes of p53 and Mdm2, as well as CDK4 and Cyclin D1, physically associated with each other. Upon combined inhibition of Mdm2 and CDK4/6, the interaction of this complex was impaired. Thus, the CDK4-Cyclin D1 complex plays a key role in enabling the transcription of p53 target genes. Taken together, our results raise caution regarding the combination of CDK4 inhibitors with Mdm2 antagonists or conventional DNA-damaging chemotherapeutics in the clinics. Moreover, they suggest a hitherto unknown role for CDK4-cyclin D1 complex in sustaining p53 activity, possibly focusing p53-mediated transcription on actively proliferating cells.

2018-09-20 | GSE113369 | GEO

MDM2 and MDM4 are Therapeutic Vulnerabilities in Malignant Rhabdoid Tumors

Project description:Malignant rhabdoid tumors (MRT) are highly aggressive pediatric cancers that respond poorly to current therapies. We screened several MRT cell lines each with large-scale RNAi, CRISPR-Cas9, and small-molecule libraries to identify potential drug targets specific for these cancers. We discovered MDM2 and MDM4, the canonical negative regulators of p53, as significant vulnerabilities. Using two compounds currently in clinical development, idasanutlin and ATSP-7041, we show that MRT cells are more sensitive than other p53 wild-type cancer cell lines to MDM2 and dual MDM2/4 inhibition in vitro. These compounds cause significant upregulation of the p53 pathway in MRT cells, and sensitivity is ablated by CRISPR-Cas9-mediated inactivation of TP53. We show that loss of SMARCB1, a subunit of the SWI/SNF (BAF) complex mutated in nearly all MRT, sensitizes cells to MDM2 and MDM2/4 inhibition by enhancing p53-mediated apoptosis. Both MDM2 and MDM2/4 inhibition slowed MRT xenograft growth in vivo, with a five-day idasanutlin pulse causing marked regression of all xenografts including durable complete responses in 50% of mice. Together, these studies identify a genetic connection between mutations in the SWI/SNF chromatin-remodeling complex and the tumor suppressor gene p53, and provide preclinical evidence to support the targeting of MDM2 and MDM4 in this often-fatal pediatric cancer.

2019-02-04 | GSE124508 | GEO

Ketogenic diet induces p53-dependent cell senescence in multiple organs

Project description:Mice on two different ketogenic diets induce p53 and cellular senescence in multiple organs, including heart and kidney. This is mediated through inactivation of MDM2 by caspase-2 cleavage, leading to p53 accumulation and induction of p21. Ketogenic diet also induced pAMPK, suggesting that persistent activation leads to p53-dependent senescence.

2024-04-12 | GSE233831 | GEO

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