Differential gain-of-function activity of three p53 hotspot mutants in vivo
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ABSTRACT:
PROVIDER: PRJNA816907 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18353600_1.fastq.gz | Fastqsanger.gz | |||
| SRR18353600_2.fastq.gz | Fastqsanger.gz | |||
| SRR18353601_1.fastq.gz | Fastqsanger.gz | |||
| SRR18353601_2.fastq.gz | Fastqsanger.gz | |||
| SRR18353602_1.fastq.gz | Fastqsanger.gz |
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Project description:To identify mutant p53 gain-of-function, primary murine osteosarcomas expressing p53 heterozygous mutants were compared to p53 heterozygous tumors. Transcriptomes regulated by different p53 hotspots were used to identify their mechanisms of action. Validation was done in cell line expressing mutant p53, to confirm its binding to transcription factors Stat3 and Egr1.
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Project description:The majority of TP53 missense mutations identified in cancer patients are in the DNA-binding domain and are characterized as either structural or contact mutations. These missense mutations exhibit inhibitory effects on wild-type p53 activity. More importantly, these mutations also demonstrate gain-of-function (GOF) activities characterized by increased metastasis, poor prognosis, and drug resistance. To better understand the activities by which TP53 mutations, identified in Li-Fraumeni syndrome, contribute to tumorigenesis, we generated mice harboring a novel germline Trp53R245W allele (contact mutation) and compared them with existing models with Trp53R172H (structural mutation) and Trp53R270H (contact mutation) alleles. Thymocytes from heterozygous mice showed that all three hotspot mutations exhibited similar inhibitory effects on wild-type p53 transcription in vivo, and tumors from these mice had similar levels of loss of heterozygosity. However, the overall survival of Trp53R245W/+ and Trp53R270H/+ mice, but not Trp53R172H/+ mice, was significantly shorter than that of Trp53+/- mice, providing strong evidence for p53-mutant-specific GOF contributions to tumor development. Furthermore, Trp53R245W/+ and Trp53R270H/+ mice had more osteosarcoma metastases than Trp53R172H/+ mice, suggesting that these two contact mutants have stronger GOF in driving osteosarcoma metastasis. Transcriptomic analyses using RNA sequencing data from Trp53R172H/+, Trp53R245W/+, and Trp53R270H/+ primary osteosarcomas in comparison with Trp53+/- indicated that GOF of the three mutants was mediated by distinct pathways. Thus, both the inhibitory effect of mutant over wild-type p53 and GOF activities of mutant p53 contributed to tumorigenesis in vivo. Targeting p53 mutant-specific pathways may be important for therapeutic outcomes in osteosarcoma.Significancep53 hotspot mutants inhibit wild-type p53 similarly but differ in their GOF activities, with stronger tumor-promoting activity in contact mutants and distinct protein partners of each mutant driving tumorigenesis and metastasis.
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Project description:We investigated the genomewide binding pattern of prevalent p53 gain-of-function (GOF) mutants by ChIP-seq, in a panel of breast cancer cell lines. We assessed the genomewide changes of H3K4me3 upon GOF p53 knockdown in MDA-MB-468 breast cancer cells bearing the p53 R273H mutation.
2015-07-31 | GSE59176 | GEO
Project description:We investigated the genomewide binding pattern of prevalent p53 gain-of-function (GOF) mutants by ChIP-seq, in a panel of breast cancer cell lines. We assessed the genomewide changes of H3K4me3 upon GOF p53 knockdown in MDA-MB-468 breast cancer cells bearing the p53 R273H mutation. This study uses ChIP-seq of H3K4me3 and histone H3 in wild-type or p53 R172H knock-in MEFs. Additionally, this study examines the transcriptome of wild-type or p53 R172H knock-in MEFs using polyA+ RNA-seq.
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Project description:TP53 (p53) is the most commonly mutated gene in human cancers, and p53 missense mutations are present in more than 40% of all human tumors. Most p53 mutations are located within the DNA binding domain, including hotspot mutations R175H, R248W, and R273H. To elucidate the precise mechanism by which p53 missense mutants execute their gain-of-functions (GOFs) in vivo, we used a proteomic screen to identify any protein that recognizes the p53 DNA-binding domain (DBD) in a manner dependent on its mutation status. To do so, we first purified the potential binding proteins associated with the p53 DBD through multi-step affinity chromatography from a SFB-p53 H1299 stable cell line. The affinity-purified SFB-p53 interacting proteins were detected by liquid chromatography mass spectrometry/mass spectrometry (LC–MS/MS) and revealed a few cellular proteins that have been reported to interact with the DNA binding domain of p53, such as TP53BP1, USP28, and Sirt1. Interestingly, we also identified many new interacting proteins from the same complex.
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Project description:TMPRSS2-ERG fusion is the most common genetic alteration in prostate cancer (PCa) and TP53 is the most frequently mutated gene in human cancers. However, their precise roles in PCa pathogenesis remain elusive. Here we showed that TMPRSS2-ERG fusion co-occurred with TP53 deletion/mutation in PCa patient specimens. ERG overexpression and Trp53 knockout/R172H mutant knockin induced pyrimidine synthesis gene (PSG) expression and prostate tumorigenesis in mice. Gain-of-function p53 mutants bound to the CTNNB1 promoter and upregulated β-Catenin. Overexpressed ERG and β-Catenin co-occupied PSG loci and mediated PSG expression, and high PSG expression associated with increased β-Catenin level and poor overall survival of PCa patients. β-Catenin inhibition by proteolysis-targeting chimeras (PROTACs) of its co-activator CBP and partner proteins LEF1/TCFs blocked ERG/p53-mutant PCa growth. Our study identifies CTNNB1 as a transcriptional target of p53 GOF-mutants, and reveals a druggable dependency on β-Catenin and pyrimidine synthesis in p53-mutated cancers with or without TMPRSS2-ERG fusion.
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Project description:The TP53 gene is frequently mutated in human cancer. Research has focused predominantly on six major “hotspot” codons, accounting for only ~30% of cancer-associated p53 mutations. To comprehensively characterize the consequences of the p53 mutation spectrum, we created a synthetically designed library and measured the functional impact of ~10,000 DNA-binding domain (DBD) p53 variants in human cells in culture and in vivo. Our results highlight the differential outcome of distinct p53 mutations in human patients and elucidate the selective pressure driving p53 conservation throughout evolution. Furthermore, while loss of anti-proliferative functionality largely correlates with the occurrence of cancer-associated p53 mutations, we observe that selective gain-of-function may further favor particular mutants in vivo. Finally, when combined with additional acquired p53 mutations, seemingly neutral TP53 SNPs may modulate phenotypic outcome and presumably tumor progression.
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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.
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Project description:TMPRSS2-ERG fusion is the most common genetic alteration in prostate cancer (PCa) and TP53 is the most frequently mutated gene in human cancers. However, their precise roles in PCa pathogenesis remain elusive. Here we showed that TMPRSS2-ERG fusion co-occurred with TP53 deletion/mutation in PCa patient specimens. ERG overexpression and Trp53 knockout/R172H mutant knockin induced pyrimidine synthesis gene (PSG) expression and prostate tumorigenesis in mice. Gain-of-function p53 mutants bound to the CTNNB1 promoter and upregulated β-Catenin. Overexpressed ERG and β-Catenin co-occupied PSG loci and mediated PSG expression, and high PSG expression associated with increased β-Catenin level and poor overall survival of PCa patients. β-Catenin inhibition by proteolysis-targeting chimeras (PROTACs) of its co-activator CBP and partner proteins LEF1/TCFs blocked ERG/p53-mutant PCa growth. Our study identifies CTNNB1 as a transcriptional target of p53 GOF-mutants, and reveals a druggable dependency on β-Catenin and pyrimidine synthesis in p53-mutated cancers with or without TMPRSS2-ERG fusion.
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