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The lung-enriched p53 mutants V157F and R158L/P regulate a novel transcriptome in lung cancer

ABSTRACT: The lung-enriched p53 mutants V157F and R158L/P regulate a novel transcriptome in lung cancer

PROVIDER: PRJNA493296 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR7906210_1.fastq.gz	Fastqsanger.gz
	SRR7906210_2.fastq.gz	Fastqsanger.gz
	SRR7906211_1.fastq.gz	Fastqsanger.gz
	SRR7906211_2.fastq.gz	Fastqsanger.gz
	SRR7906212_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

The lung-enriched p53 mutants V157F and R158L/P regulate a novel transcriptome in lung cancer

Project description:Lung cancer is the leading cause of cancer-related deaths in the US, and alterations in the tumor suppressor gene TP53 are the most frequent somatic mutation among all histologic subtypes of lung cancer. Mutations in TP53 frequently result in a protein that exhibits not only loss of tumor suppressor capability but also gain of oncogenic function (GOF). The canonical p53 hotspot mutants R175H and R273H, for example, confer upon tumors a metastatic phenotype in murine models of mutant p53. To our knowledge, GOF phenotypes of the less often studied V157, R158, and A159 mutants – which occur with higher frequency in lung cancer compared with other solid tumors – have not been defined. In this study, we aimed to define whether the lung mutants are simply equivalent to full loss of the p53 locus, or whether they additionally acquire the ability to drive new downstream effector pathways. Using a publicly available human lung cancer dataset, we characterized patients with V157, R158, and A159 p53 mutations. Additionally, we show here that cell lines with mutant p53-V157F, p53-R158L, and p53-R158P exhibit a loss of expression of canonical wildtype p53 target genes. Furthermore, these lung-enriched p53 mutants regulate genes not previously linked to p53 function including PLAU. Paradoxically, mutant p53 represses genes associated with increased cell viability, migration, and invasion. These findings collectively represent the first demonstration that lung-enriched p53 mutations at V157 and R158 regulate a novel transcriptome in human lung cancer cells and may confer de novo function.

2019-09-26 | GSE120534 | GEO

The lung-enriched p53 mutants V157F and R158L/P regulate a gain of function transcriptome in lung cancer.

Project description:Lung cancer is the leading cause of cancer-related deaths in the USA, and alterations in the tumor suppressor gene TP53 are the most frequent somatic mutation among all histologic subtypes of lung cancer. Mutations in TP53 frequently result in a protein that exhibits not only loss of tumor suppressor capability but also oncogenic gain-of-function (GOF). The canonical p53 hotspot mutants R175H and R273H, for example, confer upon tumors a metastatic phenotype in murine models of mutant p53. To the best of our knowledge, GOF phenotypes of the less often studied V157, R158 and A159 mutants-which occur with higher frequency in lung cancer compared with other solid tumors-have not been defined. In this study, we aimed to define whether the lung mutants are simply equivalent to full loss of the p53 locus, or whether they additionally acquire the ability to drive new downstream effector pathways. Using a publicly available human lung cancer dataset, we characterized patients with V157, R158 and A159 p53 mutations. In addition, we show here that cell lines with mutant p53-V157F, p53-R158L and p53-R158P exhibit a loss of expression of canonical wild-type p53 target genes. Furthermore, these lung-enriched p53 mutants regulate genes not previously linked to p53 function including PLAU. Paradoxically, mutant p53 represses genes associated with increased cell viability, migration and invasion. These findings collectively represent the first demonstration that lung-enriched p53 mutations at V157 and R158 regulate a novel transcriptome in human lung cancer cells and may confer de novo function.

| S-EPMC7316406 | biostudies-literature

Exon Array Expression Profiling of HCT116 (p53null) cells transfected with wildtype p53 and 6 p53 mutants

Project description:The tumor suppressor protein p53 functions to regulate diverse cellular processes including apoptosis, cell cycle, senescence and metabolism. Act as a master transcription factor, it can transcriptionally regulate the gene expression of many downstream target genes. p53 is frequently mutated in cancer by single nucleotide/amino acid substitutions at the DNA binding domain that result in a mutant form of p53 protein and usually loses its DNA binding and transcriptional regulation abilities. In this study, we performed gene expression analysis using Affymetrix Exon Array ST1.0 platform to assess the transcriptome of wildtype p53 and 6 loss-of-function p53 mutants in p53null HCT116 cells.

2013-08-19 | GSE49046 | GEO

Exon Array Expression Profiling of HCT116 (p53null) cells transfected with wildtype p53 and 6 p53 mutants

2013-08-19 | E-GEOD-49046 | biostudies-arrayexpress

p53

Project description:Drosophila melanogaster p53, p53, is differentially expressed in 15 experiment(s);

| FBgn0039044 | ExpressionAtlas

p53

Project description:Drosophila melanogaster p53, p53, is expressed in 3 baseline experiment(s);

| FBgn0039044 | ExpressionAtlas

RNAseq analysis for transcriptomes of ATO treated U937 cell lines expressing 10 type 1 p53 mutants, type-3 p53-R273H, p53 null, or p53 wild-type

Project description:To globally evaluate to what extend type-1 p53 mutant transcription activity can be restored by arsenic trioxide (ATO) (compared to wild-type p53), p53-null U937 cells introduced with 10 frequent type-1 p53, type-3 p53-R273H (negative control), empty vector or wild-type p53 were treated with or without 1 μg/mL ATO. mRNA was isolated and then subject to deep sequencing, using Illumina HiSeq. The sequence reads that passed quality filters were analyzed using Cutadapt. Results and conclusions: The type-1 p53 mutants are the major cellular targets of ATO in the current cell contexts. The expression profiles of well-established p53 targets in cells expressing wild-type p53 highly correlated with the ones in cells expressing ATO-rescued type-1 mutants, but not those in cells expressing ATO-treated R273H. In cells harboring type-1 mutants, the median expression levels of these targets were elevated by ATO to extents comparable to wild-type p53.

2024-08-01 | GSE182565 | GEO

Domain-specific p53 mutants activate EGFR by distinct mechanisms exposing tissue-independent therapeutic vulnerabilities

Project description:Mis-sense mutations affecting TP53 promote carcinogenesis both by inactivating its tumor suppressive functions, and by conferring aberrant pro-carcinogenic activities. We report here that mis-sense mutants in the p53 DNA-binding domain (DBD) and the transactivation domain (TAD) unexpectedly activate pro-carcinogenic epidermal growth factor receptor (EGFR) signaling via distinct, previously unrecognized molecular mechanisms. DBD- and TAD-specific TP53 mutants exhibited different cellular localization patterns and induced distinct gene expression profiles. Combining mass spectrometry with drug compound screens, we identified EGFR as a major signaling factor that is stabilized by TAD and DBD mutants in the cytosolic and nuclear compartments respectively, in a tissue-independent manner. Mechanistically, TAD mutants promote EGFR-mediated signaling by enhancing EGFR interaction with AKT via DDX31 in the cytosol. Conversely, DBD mutants maintain EGFR activity in the nucleus, by blocking EGFR interaction with the phosphatase SHP1, triggering upregulation of c-Myc and Cyclin D1 levels. Therapeutically, the sensitivity of DBD mutants to EGFR inhibition is enhanced by increasing the affinity of EGFR for SHP1, while that of TAD mutants can be induced by concurrent inhibition of AKT, mTOR or PI3K signaling. Thus, our findings suggest that gain-of-function, mis-sense mutations affecting two different p53 domains promote carcinogenesis by enhancing EGFR signaling via distinctive mechanisms. Our findings imply that cancer cells bearing domain-specific mutations may have distinct and exploitable therapeutic vulnerabilities.

2023-02-17 | PXD031725 | JPOST Repository

Insights into Allosteric Mechanisms of the Lung-Enriched p53 Mutants V157F and R158L.

Project description:Lung cancer is a leading fatal malignancy in humans. p53 mutants exhibit not only loss of tumor suppressor capability but also oncogenic gain-of-function, contributing to lung cancer initiation, progression and therapeutic resistance. Research shows that p53 mutants V157F and R158L occur with high frequency in lung squamous cell carcinomas. Revealing their conformational dynamics is critical for developing novel lung therapies. Here, we used all-atom molecular dynamics (MD) simulations to investigate the effect of V157F and R158L substitutions on the structural properties of the p53 core domain (p53C). Compared to wild-type (WT) p53C, both V157F and R158L mutants display slightly lesser β-sheet structure, larger radius of gyration, larger volume and larger exposed surface area, showing aggregation-prone structural characteristics. The aggregation-prone fragments (residues 249-267 and 268-282) of two mutants are more exposed to water solution than that of WT p53C. V157F and R158L mutation sites can affect the conformation switch of loop 1 through long-range associations. Simulations also reveal that the local structure and conformation around the V157F and R158L mutation sites are in a dynamic equilibrium between the misfolded and properly folded conformations. These results provide molecular mechanistic insights into allosteric mechanisms of the lung-enriched p53 mutants.

| S-EPMC9456101 | biostudies-literature

ECM-enriched mouse lung - TMT-based quantitative mass spectrometry analysis was performed on ECM-enriched preparation from normal murine lung, bleomycin-induced fibrotic lung, primary tumors and lymph node metastasis isolated from the KrasG12D/+p53-/- mouse model of lung adenocarcinoma. Three independent samples were processed and analyzed for each condition. This study identified ECM signatures of normal and diseased lung tissue.

Project description:TMT-based quantitative mass spectrometry analysis was performed on ECM-enriched preparation from normal murine lung, bleomycin-induced fibrotic lung, primary tumors and lymph node metastasis isolated from the KrasG12D/+p53-/- mouse model of lung adenocarcinoma. Three independent samples were processed and analyzed for each condition. This study identified ECM signatures of normal and diseased lung tissue.

2017-06-21 | PXD003517 | Pride

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