Transcriptional profiling of p53 mutants in KP LUAD cells
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ABSTRACT:
PROVIDER: PRJNA561864 | ENA |
REPOSITORIES: ENA
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Project description:Transcriptional profiling of KP LUAD cells expressing a panel of p53 mutant cDNAs.
2020-03-18 | GSE136295 | GEO
Project description:Open chromatin regions in the murine osteosarcoma cell lines expressing different mutants of p53 were identified using ATAC-seq
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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
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
Project description:Increasing evidence highlights the role of bacteria in the physiopathology of cancer. However, the underlying molecular mechanisms remains poorly understood. Several cancer-associated bacteria have been shown to produce toxins which modulate the tumor suppressor p53 and thereby interfere with the host defense against tumorigenesis. Here, we show that lipopolysaccharides from Klebsiella pneumoniae (Kp) strongly inhibit the host p53 pathway and impairs p53 transcriptional activity upon DNA damage and oncogenic stress, preventing its tumor suppressive function.
2022-02-26 | GSE174531 | GEO
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
Project description:Lung cancer is the leading cause of cancer deaths worldwide. TP53 tumor suppressor gene mutations occur in 50% of lung adenocarcinomas (LUADs) and are linked to poor prognosis, but how p53 suppresses LUAD development remains enigmatic. We show here that p53 suppresses LUAD by governing cell state, by promoting alveolar type 1 (AT1) differentiation. Using mice expressing oncogenic Kras and null, wild-type, or hypermorphic p53 alleles in alveolar type 2 (AT2) cells, we observed graded effects of p53 on LUAD initiation and progression. RNA-sequencing and ATAC-sequencing of LUAD cells uncovered a p53-induced AT1 differentiation program during tumor suppression in vivo through direct DNA binding, chromatin remodeling, and AT1 gene induction. Single-cell transcriptomics analyses revealed that during LUAD evolution, p53 promotes AT1 differentiation through action in a transitional cell state analogous to a transient intermediary seen during AT2-to-AT1 differentiation in alveolar injury repair. Notably, p53 inactivation resulted in the inappropriate persistence of these transitional cancer cells accompanied by upregulated growth signaling and divergence from lung lineage identity, characteristics associated with LUAD progression. Analysis of p53wt and p53-null mice showed that p53 also directs alveolar regeneration after injury, by regulating AT2 self-renewal and promoting transitional cell differentiation into AT1 cells. Collectively, these findings illuminate mechanisms of p53-mediated LUAD suppression, in which p53 governs alveolar differentiation, and suggest that tumor suppression reflects a fundamental role of p53 in orchestrating tissue repair after injury.
2023-05-04 | GSE231671 | GEO
Project description:Lung cancer is the leading cause of cancer deaths worldwide. TP53 tumor suppressor gene mutations occur in 50% of lung adenocarcinomas (LUADs) and are linked to poor prognosis, but how p53 suppresses LUAD development remains enigmatic. We show here that p53 suppresses LUAD by governing cell state, by promoting alveolar type 1 (AT1) differentiation. Using mice expressing oncogenic Kras and null, wild-type, or hypermorphic p53 alleles in alveolar type 2 (AT2) cells, we observed graded effects of p53 on LUAD initiation and progression. RNA-sequencing and ATAC-sequencing of LUAD cells uncovered a p53-induced AT1 differentiation program during tumor suppression in vivo through direct DNA binding, chromatin remodeling, and AT1 gene induction. Single-cell transcriptomics analyses revealed that during LUAD evolution, p53 promotes AT1 differentiation through action in a transitional cell state analogous to a transient intermediary seen during AT2-to-AT1 differentiation in alveolar injury repair. Notably, p53 inactivation resulted in the inappropriate persistence of these transitional cancer cells accompanied by upregulated growth signaling and divergence from lung lineage identity, characteristics associated with LUAD progression. Analysis of p53wt and p53-null mice showed that p53 also directs alveolar regeneration after injury, by regulating AT2 self-renewal and promoting transitional cell differentiation into AT1 cells. Collectively, these findings illuminate mechanisms of p53-mediated LUAD suppression, in which p53 governs alveolar differentiation, and suggest that tumor suppression reflects a fundamental role of p53 in orchestrating tissue repair after injury.
2023-05-04 | GSE231677 | GEO
Project description:Lung cancer is the leading cause of cancer deaths worldwide. TP53 tumor suppressor gene mutations occur in 50% of lung adenocarcinomas (LUADs) and are linked to poor prognosis, but how p53 suppresses LUAD development remains enigmatic. We show here that p53 suppresses LUAD by governing cell state, by promoting alveolar type 1 (AT1) differentiation. Using mice expressing oncogenic Kras and null, wild-type, or hypermorphic p53 alleles in alveolar type 2 (AT2) cells, we observed graded effects of p53 on LUAD initiation and progression. RNA-sequencing and ATAC-sequencing of LUAD cells uncovered a p53-induced AT1 differentiation program during tumor suppression in vivo through direct DNA binding, chromatin remodeling, and AT1 gene induction. Single-cell transcriptomics analyses revealed that during LUAD evolution, p53 promotes AT1 differentiation through action in a transitional cell state analogous to a transient intermediary seen during AT2-to-AT1 differentiation in alveolar injury repair. Notably, p53 inactivation resulted in the inappropriate persistence of these transitional cancer cells accompanied by upregulated growth signaling and divergence from lung lineage identity, characteristics associated with LUAD progression. Analysis of p53wt and p53-null mice showed that p53 also directs alveolar regeneration after injury, by regulating AT2 self-renewal and promoting transitional cell differentiation into AT1 cells. Collectively, these findings illuminate mechanisms of p53-mediated LUAD suppression, in which p53 governs alveolar differentiation, and suggest that tumor suppression reflects a fundamental role of p53 in orchestrating tissue repair after injury.
2023-05-04 | GSE231676 | GEO