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: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.
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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. 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:Mutant p53 proteins, resulting from the missense mutations of the TP53 tumor suppressor gene, possess gain-of-function activities and are among the most robust oncoproteins in human tumors. They are potentially important therapeutic targets. No studies to date have distinguished common, therapeutically relevant mutant p53 gain-of-function effects from effects specific to different mutant variants and cell backgrounds. here we perform the analysis of transcriptomes,rRegardless of the cell background, of different mutant p53s.
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Project description:Mutant p53 proteins, resulting from the missense mutations of the TP53 tumor suppressor gene, possess gain-of-function activities and are among the most robust oncoproteins in human tumors. They are potentially important therapeutic targets. No studies to date have distinguished common, therapeutically relevant mutant p53 gain-of-function effects from effects specific to different mutant variants and cell backgrounds. here we performed RNA-seq analysisin MDA-MB-231 (R280K) upon silencing TP53 or the control siRNA.
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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:Mutant p53 proteins, resulting from the missense mutations of the TP53 tumor suppressor gene, possess gain-of-function activities and are among the most robust oncoproteins in human tumors. They are potentially important therapeutic targets. To complement our mutant p53 transcriptomic studies we have performed ChIP-seq analysis in MDA-MB-231 (R280K) using the mouse anti-p53 DO1 antibody or control mouse IgG versus the input material.
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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:Mutant p53 proteins, resulting form frequent TP53 tumor suppressor missense mutations, possess gain-of-function activities and are among the most widespread and robust oncoproteins in human tumors. They are potentially important but understudied therapeutic targets. No studies to date have distinguished common, therapeutically relevant mutant p53 gain-of-function effects, from effects specific to different mutant variants and cell backgrounds. Here we identify 26S proteasome machinery as the common downstream effector controlled by mutant p53s in Triple Negative Breast Cancer (TNBC - aggressive carcinomas with TP53 as the most frequently mutated locus) and conserved in other human cancers. We have identified this pathway using a combination of single-model, multi-method vertical analysis (whole cell proteome, RNA sequencing an ChIP sequencing) and multi-cell line, horizontal analysis of transcriptiomes. We found that different missense mutant p53s regardless of the cell background transcriptionaly activate whole 26S proteasome machinery. Proteasome activity is significantly increased in p53 mutant versus wild-type or knockdown/null status - in cellular and mouse models as well as in human breast tumors. Increased proteasome activity leads to inhibition of tumor suppressive pathways. The control of mutant p53 over proteasome transcription and activity results in the increased resistance to proteasome inhibitors. By combining the mutant p53 targeting agents and proteasome inhibitor we were able to overcome the “bounce-back” proteasome inhibitor resistance mechanism in mutant p53 bearing TNBC cells and xenografts in vivo.
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