Residual apoptotic activity of a tumorigenic p53 mutant improves cancer therapy responses
Ontology highlight
ABSTRACT:
SUBMITTER: Dr. Oleg Timofeev
PROVIDER: S-SCDT-EMBOJ-2019-102096 | biostudies-other |
REPOSITORIES: biostudies-other
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Project description:Engineered p53 mutant mice are valuable tools for delineating p53 functions in tumor suppression and cancer therapy. Here, we have introduced the R178E mutation into the Trp53 gene of mice to specifically ablate the cooperative nature of p53 DNA binding. Trp53R178E mice show no detectable target gene regulation and, at first sight, are largely indistinguishable from Trp53-/- mice. Surprisingly, stabilization of p53R178E in Mdm2-/- mice nevertheless triggers extensive apoptosis, indicative of residual wild-type activities. Although this apoptotic activity suffices to trigger lethality of Trp53R178E ;Mdm2-/- embryos, it proves insufficient for suppression of spontaneous and oncogene-driven tumorigenesis. Trp53R178E mice develop tumors indistinguishably from Trp53-/- mice and tumors retain and even stabilize the p53R178E protein, further attesting to the lack of significant tumor suppressor activity. However, Trp53R178E tumors exhibit remarkably better chemotherapy responses than Trp53-/- ones, resulting in enhanced eradication of p53-mutated tumor cells. Together, this provides genetic proof-of-principle evidence that a p53 mutant can be highly tumorigenic and yet retain apoptotic activity which provides a survival benefit in the context of cancer therapy.
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Project description:Mutations in the p53 tumor suppressor protein are highly frequent in tumors and often endow cells with tumorigenic capacities. We sought to examine a possible role for mutant p53 in the cross-talk between cancer cells and their surrounding stroma, which is a crucial factor affecting tumor outcome. Here we present a novel model which enables individual monitoring of the response of cancer cells and stromal cells (fibroblasts) to co-culturing. We found that fibroblasts elicit the interferon beta (IFNβ) pathway when in contact with cancer cells, thereby inhibiting their migration. Mutant p53 in the tumor was able to alleviate this response via SOCS1 mediated inhibition of STAT1 phosphorylation. IFNβ on the other hand, reduced mutant p53 RNA levels by restricting its RNA stabilizer, WIG1. These data underscore mutant p53 oncogenic properties in the context of the tumor microenvironment and suggest that mutant p53 positive cancer patients might benefit from IFNβ treatment.
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Project description:The tumor suppressor gene TP53 is the most frequently mutated gene in numerous cancer types, including prostate cancer (PCa). Specifically, missense mutations in TP53 are selectively enriched in PCa, and cluster to particular "hot spots" in the p53 DNA binding domain with mutation at the R273 residue occurring most frequently. While this residue is similarly mutated to R273C-p53 or R273H-p53 in all cancer types examined, in PCa selective enrichment of R273C-p53 is observed. Importantly, examination of clinical datasets indicated that TP53 heterozygosity can either be maintained or loss of heterozygosity (LOH) occurs. Thus, to mimic tumor-associated mutant p53, R273C-p53 and R273H-p53 isogenic PCa models were developed in the presence or absence of wild-type p53. In the absence of wild-type p53, both R273C-p53 and R273H-p53 exhibited similar loss of DNA binding, transcriptional profiles, and loss of canonical tumor suppressor functions associated with wild-type p53. In the presence of wild-type p53 expression, both R273C-p53 and R273H-p53 supported canonical p53 target gene expression yet elicited distinct cistromic and transcriptional profiles when compared to each other. Moreover, heterozygous modeling of R273C-p53 or R273H-p53 expression resulted in distinct phenotypic outcomes in vitro and in vivo. Thus, mutant p53 acts in a context-dependent manner to elicit pro-tumorigenic transcriptional profiles, providing critical insight into mutant p53-mediated prostate cancer progression.
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Project description:Mutations in the p53 tumor suppressor protein are highly frequent in tumors and often endow cells with tumorigenic capacities. We sought to examine a possible role for mutant p53 in the cross-talk between cancer cells and their surrounding stroma, which is a crucial factor affecting tumor outcome. Here we present a novel model which enables to individually monitor the response of cancer cells and stromal cells (fibroblasts) to co-culturing. We found that fibroblasts elicit the interferon beta (IFNβ) pathway when in contact with cancer cells, thereby inhibiting their migration. Mutant p53 in the tumor was able to alleviate this response via SOCS1 mediated inhibition of STAT1 phosphorylation. IFNβ on the other hand, reduced mutant p53 RNA levels by restricting its RNA stabilizer, WIG1. These data underscore mutant p53 oncogenic properties in the context of the tumor microenvironment and suggest that mutant p53 positive cancer patients might benefit from IFNβ treatment. As we planned to investigate the effect of mutant p53 we chose to work with lung cancer cells (H1299) which are null for p53 expression and introduce them with two p53 ‘hotsopt’ mutations residing within the DNA binding domain namely R175H and R248Q (H1299175 and H1299248 respectively, Figure 1A and B). The cells were then labeled with a red fluorescent protein (dsRed), while lung CAFs (HK3-T) were labeled with a green fluorescent protein (GFP). The labeled populations were co-cultivated for 24 hours and separated by Fluorescence Associated Cell Sorting (FACS) based on their specific fluorescent marker. RNA was extracted and samples were loaded on chips. Samples were loaded against a common reference sample which contained equal amount of RNA from all samples.
| S-ECPF-GEOD-41477 | biostudies-other
Project description:Previous studies have demonstrated that deletion of Cryptochromes (CRY) protects p53-/- mutant mice from early onset of cancer and extends their median lifespan by about 1.5 fold. In vitro studies had revealed that deletion of CRY enhances apoptosis in response to UV damage through activation of p73, and inactivation of GSK3β. However, it was not known at the transcriptome-wide level how CRY deletion delays the onset of cancer in p53-/- mutant mice. In this study, an RNA-seq approach was taken to identify the differentially regulated genes and pathways in p53-/- and p53-/-Cry1-/-Cry2-/- mouse embryonic fibroblasts following UV-induced DNA damage. Gene Set Enrichment Analysis demonstrated that immune surveillance associated genes regulated by IFN-γ showed increased responses, as well as genes involved in TNFα signaling via NF-κB. Protein network analysis helped identify key genes such as p21, Egr3, Sirt1, Jun and Casp1 among differentially regulated genes, and revealed their interaction partners. Collectively, the present study suggests that additional genes involved in NF-κB regulation, IFN-γ response, as well as non-coding RNAs may contribute to delaying the onset of cancer in p53-/-Cry1-/-Cry2-/- mice compared to p53-/- mutant mice.
2018-10-01 | GSE115102 | GEO
Project description:Over 50% cancer bears TP53 mutation, the highly stabilized mutant p53 protein drives the tumorigenesis and progression. Mutation of p53 not only cause loss-of-function and dominant-negative effects (DNE), but also results in the abnormal stability by the regulation of the ubiquitin-proteasome system and molecular chaperones that promote tumorigenesis through gain-of-function effects. The accumulation of mutant p53 is mainly regulated by molecular chaperones, including Hsp40, Hsp70, Hsp90 and other biomolecules such as TRIM21, BAG2 and Stat3. In addition, mutant p53 forms prion-like aggregates or complexes with other protein molecules and result in the accumulation of mutant p53 in tumor cells. Depleting mutant p53 has become one of the strategies to target mutant p53. This review will focus on the mechanism of mutant p53 stabilization and discuss how the strategies to manipulate these interconnected processes for cancer therapy.
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Project description:BACKGROUND:There is currently no clinical distinction between different TP53 mutations, despite increasing evidence that not all mutations have equally deleterious effects on the activity of the encoded tumor suppressor protein p53. The objective of this study was to determine whether these biological differences have clinical significance. METHODS:This retrospective cohort analysis included 2,074 patients with sporadic TP53 mutations (403 unique mutations) and 1,049 germline TP53 mutation carriers (188 unique mutations). Survival was projected by stratifying patients according to their p53 mutant-specific residual transcriptional activity scores. RESULTS:Pan-cancer survival analyses revealed a strong association between increased mutant p53 residual activity and improved survival in males with glioma and gastric adenocarcinoma (P = 0.002 and P = 0.02) that was not present in the female cohorts (P = 0.16 and P = 0.50). Male glioma and gastric cancer patients with TP53 mutations resulting in >5% transcriptional activity had 3.1-fold (95% CI, 2.4-3.8; P = 0.002; multivariate analysis hazard ratio [HR]) and 4.6-fold (95% CI, 3.7-5.6; P = 0.001; multivariate analysis HR) lower risk of death as compared with patients harboring inactive (0% activity) p53 mutants. The correlation between mutant p53 residual activity with survival was recapitulated in the dataset of germline TP53 mutation carriers (HR = 3.0, 95% CI, 2.7-3.4, P < 0.001 [females]; HR = 2.2, 95% CI, 1.8-2.6, P < 0.001 [males]), where brain and gastric tumors were more common among males (P < 0.001 and P = 0.001, respectively). CONCLUSION:The retention of mutant p53 transcriptional activity prognosticates superior survival for men with glioma and gastric adenocarcinoma harboring sporadic TP53 mutations. Among germline TP53 mutation carriers, increased residual transcriptional activity is correlated with prolonged lifetime cancer survival and delayed tumor onset, and males are more prone to develop brain and gastric tumors. FUNDING:Canadian Institutes of Health Research (no. 148556).
| S-EPMC6129128 | biostudies-literature
Project description:p53 mutations are believed to correlate with poor patient survival, as mutations abolish the transcriptional function of wild-type p53 in the DNA damage response and mutant p53 gain-of-function activities enhance drug resistance. Moreover, p53 also exhibits non-transcriptional apoptotic activity with yet unclear in vivo relevance for tumor suppression and cancer therapy. We have generated mice expressing a unique p53 mutant (R178E, human R181E) that is DNA binding deficient without alterations in the global structure or DNA binding surface. The aim of this study is to use this new mouse model to demonstrate that a DNA binding-deficient p53 mutant can drive tumor development while retaining non-transcriptional apoptotic activities.
2019-09-03 | E-MTAB-6774 | biostudies-arrayexpress
Project description:TP53 is a critical tumor-suppressor gene that is mutated in more than half of all human cancers. Mutations in TP53 not only impair its antitumor activity, but also confer mutant p53 protein oncogenic properties. The p53-targeted therapy approach began with the identification of compounds capable of restoring/reactivating wild-type p53 functions or eliminating mutant p53. Treatments that directly target mutant p53 are extremely structure and drug-species-dependent. Due to the mutation of wild-type p53, multiple survival pathways that are normally maintained by wild-type p53 are disrupted, necessitating the activation of compensatory genes or pathways to promote cancer cell survival. Additionally, because the oncogenic functions of mutant p53 contribute to cancer proliferation and metastasis, targeting the signaling pathways altered by p53 mutation appears to be an attractive strategy. Synthetic lethality implies that while disruption of either gene alone is permissible among two genes with synthetic lethal interactions, complete disruption of both genes results in cell death. Thus, rather than directly targeting p53, exploiting mutant p53 synthetic lethal genes may provide additional therapeutic benefits. Additionally, research progress on the functions of noncoding RNAs has made it clear that disrupting noncoding RNA networks has a favorable antitumor effect, supporting the hypothesis that targeting noncoding RNAs may have potential synthetic lethal effects in cancers with p53 mutations. The purpose of this review is to discuss treatments for cancers with mutant p53 that focus on directly targeting mutant p53, restoring wild-type functions, and exploiting synthetic lethal interactions with mutant p53. Additionally, the possibility of noncoding RNAs acting as synthetic lethal targets for mutant p53 will be discussed.
| S-EPMC8480024 | biostudies-literature
Project description:Mutations in the p53 tumor suppressor protein are highly frequent in tumors and often endow cells with tumorigenic capacities. We sought to examine a possible role for mutant p53 in the cross-talk between cancer cells and their surrounding stroma, which is a crucial factor affecting tumor outcome. Here we present a novel model which enables to individually monitor the response of cancer cells and stromal cells (fibroblasts) to co-culturing. We found that fibroblasts elicit the interferon beta (IFNβ) pathway when in contact with cancer cells, thereby inhibiting their migration. Mutant p53 in the tumor was able to alleviate this response via SOCS1 mediated inhibition of STAT1 phosphorylation. IFNβ on the other hand, reduced mutant p53 RNA levels by restricting its RNA stabilizer, WIG1. These data underscore mutant p53 oncogenic properties in the context of the tumor microenvironment and suggest that mutant p53 positive cancer patients might benefit from IFNβ treatment. As we planned to investigate the effect of mutant p53 we chose to work with lung cancer cells (H1299) which are null for p53 expression and introduce them with two p53 ‘hotsopt’ mutations residing within the DNA binding domain namely R175H and R248Q (H1299175 and H1299248 respectively, Figure 1A and B). The cells were then labeled with a red fluorescent protein (dsRed), while lung CAFs (HK3-T) were labeled with a green fluorescent protein (GFP). The labeled populations were co-cultivated for 24 hours and separated by Fluorescence Associated Cell Sorting (FACS) based on their specific fluorescent marker. RNA was extracted and samples were loaded on chips. Samples were loaded against a common reference sample which contained equal amount of RNA from all samples.
2013-10-10 | E-GEOD-41477 | biostudies-arrayexpress