Lack of major genome instability in tumors of p53 null rats
Ontology highlight
ABSTRACT:
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| ERR455192.fastq.gz | Fastqsanger.gz | |||
| ERR455193.fastq.gz | Fastqsanger.gz | |||
| ERR455195.fastq.gz | Fastqsanger.gz | |||
| ERR455197.fastq.gz | Fastqsanger.gz |
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Project description:Tumorigenesis is often associated with loss of tumor suppressor genes (such as TP53), genomic instability and telomere lengthening. Previously, we generated and characterized a rat p53 knockout model in which the homozygous rats predominantly develop hemangiosarcomas whereas the heterozygous rats mainly develop osteosarcomas. Using genome-wide analyses, we find that the tumors that arise in the heterozygous and homozygous Tp53C273X mutant animals are also different in their genomic instability profiles. While p53 was fully inactivated in both heterozygous and homozygous knockout rats, tumors from homozygous animals show very limited aneuploidy and low degrees of somatic copy number variation as compared to the tumors from heterozygous animals. In addition, complex structural rearrangements such as chromothripsis and breakage-fusion-bridge cycles were never found in tumors from homozygous animals, while these were readily detectable in tumors from heterozygous animals. Finally, we measured telomere length and telomere lengthening pathway activity and found that tumors of homozygous animals have longer telomeres but do not show clear telomerase or alternative lengthening of telomeres (ALT) activity differences as compared to the tumors from heterozygous animals. Taken together, our results demonstrate that host p53 status in this rat p53 knockout model has a large effect on both tumor type and genomic instability characteristics, where full loss of functional p53 is not the main driver of large-scale structural variations. Our results also suggest that chromothripsis primarily occurs under p53 heterozygous rather than p53 null conditions.
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Project description:Seeds, including soybean (Glycine max), contain bioactive proteins with anti-nutritional and immunological properties that affect metabolism and assimilation of seed derived nutrients and as allergens that can induce escalating adverse immune responses. The presence of anti-nutritional proteins requires soybean protein to be processed by heat that results in energy costs and alteration of soybean protein’s physiochemical properties. Nulls for bioactive seed proteins have been isolated from the USDA soybean collection including Kunitz trypsin inhibitor (TI) and soybean agglutinin (LE) and immunodominant soybean allergen P34 proteins. Each of these nulls has the potential to partially address concerns of soybean feed/food consumption and stacked together these traits can form a basis for engineering improved soybean cultivars. A stack of cultivars of recessive nulls of TI, LE, and P34 was created in a cv Williams 82 background termed “Triple Null”. The reduction of these proteins slightly diminishes the overall protein content of the seed that was analyzed by 2D IEF/SDS gels and proteomics. P34 and Kunitz Trypsin Inhibitor nulls are frame shift mutants shown by mass spectroscopy to accumulate small amounts of authentic protein. Triple Null’s capacity for biolistic transformation was assessed showing that Triple Null can be transformed permitting stacking of transgene traits. Triple Null has possible application as a conventional feed/food source and for immunotherapy to mitigate soybean allergenic response and be leveraged as a transformation platform to stack other production or consumer traits.
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Project description:Lack of major genome-wide DNA methylation changes in succinate-treated human epithelial cells
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Project description:P53 independent P21 expression deregulates replication licensing , leading to genomic instability
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Project description:We performed an RNA-Seq analysis comparing thymic lymphoma tissues from the p53-null(n=2) and ΔNp63Δ/Δ;p53-/- (n=3) or ΔNp73Δ/Δ;p53-/-(n=3). Mice at 10 weeks of age were injected with either Ad-mCherry or Ad-CRE-mCherry to delete ΔNp63/ΔNp73 in the thymic lmyphomas. We aimed to test by deleting the DNp63/DNp73 in these p53-deficient tumors will mediate tumor regression and analyze the expression profile of the genes
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Project description:Glioblastoma (GBM) is a highly lethal brain tumor presenting as one of two subtypes with distinct clinical histories and molecular profiles. The primary GBM subtype presents acutely as high-grade disease that typically harbors EGFR, PTEN and Ink4a/Arf mutations, and the secondary GBM subtype evolves from the slow progression of low-grade disease that classically possesses PDGF and p53 events1. Here, we show that concomitant CNS-specific deletion of p53 and Pten in the mouse CNS generates a penetrant acute-onset high-grade malignant glioma phenotype with striking clinical, pathological and molecular resemblance to primary GBM in humans. This genetic observation prompted p53 and PTEN mutational analysis in human primary GBM, demonstrating unexpectedly frequent inactivating mutations of p53 as well the expected PTEN mutations. Integrated transcriptomic profling, in silico promoter analysis and functional studies of murine neural stem cells (NSCs) established that dual, but not singular, inactivation of p53 and Pten promotes an undifferentiated state with high renewal potential and drives elevated c-Myc levels and its associated signature. Functional studies validated increased c-Myc activity as a potent contributor to the impaired differentiation and enhanced renewal of p53-Pten null NSCs as well as tumor neurospheres (TNSs) derived from this model. c-Myc also serves to maintain robust tumorigenic potential of p53-Pten null TNSs. These murine modeling studies, together with confirmatory transcriptomic/promoter studies in human primary GBM, validate a pathogenetic role of a common tumor suppressor mutation profile in human primary GBM and establish c-Myc as a key target for cooperative actions of p53 and Pten in the regulation of normal and malignant stem/progenitor cell differentiation, self-renewal and tumorigenic potential. We used microarrays to detail the gene expression difference of the p53-null and p53/Pten-doubly null neural stem cell after differentiation . Experiment Overall Design: transcriptome comparisons of 2 independent p53-null with 3 p53/Pten double-null murine NSCs at 1 day post exposure to the differentiation inducer.
2008-10-26 | E-GEOD-12694 | biostudies-arrayexpress