The DOI matches its Crossref record; 31 of the 31 references it cites were found in a registry or an index.
Restoration of p53 function leads to tumour regression in vivo
Abstract
Tumorigenesis is a multi-step process that requires activation of oncogenes and inactivation of tumour suppressor genes. Mouse models of human cancers have recently demonstrated that continuous expression of a dominantly acting oncogene (for example, Hras, Kras and Myc) is often required for tumour maintenance; this phenotype is referred to as oncogene addiction. This concept has received clinical validation by the development of active anticancer drugs that specifically inhibit the function of oncoproteins such as BCR-ABL, c-KIT and EGFR. Identifying additional gene mutations that are required for tumour maintenance may therefore yield clinically useful targets for new cancer therapies. Although loss of p53 function is a common feature of human cancers, it is not known whether sustained inactivation of this or other tumour suppressor pathways is required for tumour maintenance. To explore this issue, we developed a Cre-loxP-based strategy to temporally control tumour suppressor gene expression in vivo. Here we show that restoring endogenous p53 expression leads to regression of autochthonous lymphomas and sarcomas in mice without affecting normal tissues. The mechanism responsible for tumour regression is dependent on the tumour type, with the main consequence of p53 restoration being apoptosis in lymphomas and suppression of cell growth with features of cellular senescence in sarcomas. These results support efforts to treat human cancers by way of pharmacological reactivation of p53.
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In the citing paper
“Interestingly, some tumor cells retain the ability to senesce in response to DNA-damaging chemotherapy or p53 reactivation; in mice, this response arrests tumor progression [ 20 – 22 ].”
From Senescence-Associated Secretory Phenotypes Reveal Cell-Nonautonomous Functions of Oncogenic RAS and the p53 Tumor Suppressor (2008) · cites this paper as [21]
In the citing paper
“Recent findings show that tumors induced to senesce in mice gradually regress [ 21 , 22 ], owing perhaps to infiltration by cells of the innate immune system [ 22 ].”
From Senescence-Associated Secretory Phenotypes Reveal Cell-Nonautonomous Functions of Oncogenic RAS and the p53 Tumor Suppressor (2008) · cites this paper as [21]
In the citing paper
“The tumour suppressor p53-p21 axis cell- autonomously controls the OIS response, but additionally mediates communication between senescent cells and immune cells, presumably via the SASP 144-146 .”
From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [144]
In the citing paper
“Specifically, restoration of Tp53 in mouse models of lymphoma and sarcoma led to tumour regression with features of cellular senescence, thereby implying that p53- mediated apoptosis and senescence- evoked immune clearance are the underlying mechanisms 144 .”
From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [144]
In the citing paper
“the outcome of endogenous p53 reactivation can be senescence and/or cell death depending on the tumour type 35,141,142”
From Inside and out: the activities of senescence in cancer (2014) · cites this paper as [35]
In the citing paper
“This notion that p53 is able to activate different checkpoint programs in different tissues is supported by the observation that restoration of endogenous p53 function in p53 null mice activates primarily an apoptotic response to inhibit T-cell lymphomas, while inhibition of sarcomas requires activation of a cellular senescence program60.”
From Telomere dysfunction and tumour suppression: the senescence connection (2008) · cites this paper as [60]
In the citing paper
“In addition, the reactivation of p53-dependent senescence promotes the regression of established p53-deficient tumors, 186 facilitated by SASP-assisted recruitment of innate cells (natural killer [NK] cells and M4) to the tumor bed.187”
From Meta-hallmarks of aging and cancer (2023) · cites this paper as [186]
In the citing paper
“Mouse models clearly demonstrate that the inactivation of p53 promotes tumorigenesis, whereas restoration of p53 causes the regression of established tumours78–80.”
From MDM2, MDMX and p53 in oncogenesis and cancer therapy (2013) · cites this paper as [79]
In the citing paper
“Another recent surprise was the rapid in vivo clearance of tumour cells that undergo P53-triggered senescence 10, 11”
From The common biology of cancer and ageing (2007) · cites this paper as [11]
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“Loss of functional TP53 has profound impacts on the cellular control of cell cycle progression and apoptosis and contributes to malignant conversion.(1) Emerging evidence also implicates TP53 in the induction of immunogenic cell death and regulation of expression of a number of genes involved in antigen processing and…”
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Discussion of some ‘knowns’ and some ‘unknowns’ about the tumour suppressor p53
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“We crossed Ng2/Cspg4 / , Ng2/Cspg4 (32, 47), LSL-Kras; p53 (29), Kras; p53 (48, 49), and R26 or Col1a1 transgenic mice.”
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“In the battle against cancer, p53 constitutes one of the most important strategic targets, as once p53 is activated, the cancer cell is suppressed (Ventura et al., 2007).”
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“1-iCOUNT animals were crossed to Gli1:Cre-ER mice (Jackson Lab No 007913: (Ahn and Joyner, 2004) and ROSA26:Cre-ER mice (Jackson Lab No 008463; (Ventura et al., 2007).”
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Smarcd3 is an epigenetic modulator of the metabolic landscape in pancreatic ductal adenocarcinoma
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“In fact, the overexpressions of MDM2 and MDMX contribute to the loss of p53 activation and tumor survival in tumors [7,8].”
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“cases, disruption of the MDM2:p53 interaction has been shown to stabilize and activate the transcriptional activity of p53 leading to cell death or to G1/G2 cell cycle arrest [5,6].”
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“The significance of reactivating senescence for tumor regression has already been proven in three distinct p53-defective mouse models: hepatocarcinoma, lymphoma, and sarcoma (Martins et al., 2006; Ventura et al., 2007; Xue et al., 2007).”
BackgroundMAGED2: A novel p53-dissociator
McLeod, H. L., Culverhouse, R., Zhang, W., Zeng, J., Brachmann, R. K., & Papageorgio, C. (2007) · International Journal of Oncology · doi:10.3892/ijo.31.5.1205 · Cited by 26
“Restoration of p53 function has already been demonstrated to lead tumor regression in vivo (47).”
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“Exceptions include a number of secreted factors, including cytokines and chemokines (Acosta et al., 2008; Coppé et al., 2008; Kuilman et al., 2008; Wajapeyee et al., 2008; Ye et al., 2007), which are regulated during, and appear to play a role in the mechanism of, senescence in vitro and in vivo.”
BackgroundTranscriptional Regulation by Mutant p53 and Oncogenesis
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“Several groups have shown that reactivation of p53 in p53-defi cient cells can induce senescence or apoptosis [ 46 , 66 , 75 , 77 , 84 ].”
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“Additional mouse strains used were FVB/NJ, C57BL/6, RARE-lacZ and Cre-ERT2, all obtained from Jackson Laboratories and maintained at the University of Louisville.”
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GOF Mutant p53 in Cancers: A Therapeutic Challenge
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“Interestingly, even though some of the p53 gene therapy’s WT-p53 protein expression in only some cells, secondary effects in inducing systemic immunological response led to long-lasting effects on tumour regression [55,57].”
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“Indeed, p53deficient tumors regress when the p53 level is rescued in vivo [22, 63].”
BackgroundNucleases in homologous recombination as targets for cancer therapy
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“Cancer cells are also capable of inhibiting apoptosis, thus making treatment with DNA-damaging agents and DNA-repair inhibitors ineffective [208,209], unless an excessive amount of damage leads to mitotic catastrophe due to a loss of essential genetic material.”
BackgroundArrested development and the great escape – The role of cellular senescence in pancreatic cancer
Moir, J. A. G., White, S. A., & Mann, J. (2014) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2014.10.018 · Cited by 26
Oncogene-Induced Senescence and its Role in Tumor Suppression
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“Indeed, several reports have shown that reactivation of conditionally inactivated p53 in mice bearing sarcomas and hepatic carcinomas led to the regression of these cancers via senescence [83, 84].”
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“Consistent with this notion, two groups recently showed that the restoration p53 function in tumors lacking functional p53 induces tumor regression by premature senescence [18,19].”
BackgroundHuman colorectal cancer derived-MSCs promote tumor cells escape from senescence via P53/P21 pathway
Li, G., Zhang, R., Zhang, X., Shao, S., Hu, F., & Feng, Y. (2019) · Clinical & Translational Oncology · doi:10.1007/s12094-019-02152-5 · Cited by 25
Advances in Cancer Treatment Through Nanotheranostics and Emerging Therapies
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“Restoring genes, like p53, promote tumor regression [241,242].”
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“Numerous studies in murine cancer models have shown that restoration of wild type p53 function in tumors is highly therapeutic (45,46).”
BackgroundLi, X., Li, B., Ni, Z., Zhou, P., Wang, B., He, J., Xiong, H., Yang, F., Wu, Y., Lyu, X., et al. (2017) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-16-0763 · Cited by 23
“Although experimental reactivation of p53 can lead to profound tumor regression (2, 3), very few effective targeted strategies have been developed for p53-defective cancers.”
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Differential p53-Mediated Cellular Responses to DNA-Damaging Therapeutic Agents
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“, in inducible transgenic models [16,17], gene therapy [18,19] or by use of p53 pathwayrestoring therapeutic agents [20,21].”
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“First, to study hepatocyte proliferation throughout the liver lobule, we employed an inducible, R26-CreERT2 (Ventura et al., 2007) allele to permanently and randomly label cells with one of the four fluorophores in the R26-Confetti allele (Snippert et al., 2010).”
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“The concept of restoration of wild-type p53 function in tumors is greatly strengthened by mouse model studies.(11,12)”
BackgroundMdm2 exerts pro-apoptotic activities by antagonizing insulin-like growth factor-I-mediated survival
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Adenoviral Delivery of the EMX2 Gene Suppresses Growth in Human Gastric Cancer
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“It is noteworthy that the delivery system we used for the treatment was recombinant adenovirus serotype 5 (Ad5), the most frequently used vector in several types of cancer gene therapy [11,12,34,35].”
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“Importantly, restoration of p53 activity results in tumor regression but it should be remembered that tumors may be able to quickly generate resistance by finding other ways to abrogate the p53 pathway [24, 25].”
BackgroundUsing targeted transgenic reporter mice to study promoter-specific p53 transcriptional activity
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“Given the tumor suppressive potential of senescence, discovering novel senescence-inducing interventions for the treatment of cancer including sarcomas is of great interest.(43) Whether trabectedin with additional hyperthermia offers such intervention in p53-proficient tumor cells—as seen in U2OS—has to be addressed f…”
Background14-3-3β Depletion Drives a Senescence Program in Glioblastoma Cells Through the ERK/SKP2/p27 Pathway
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Rac1 targeting suppresses p53 deficiency–mediated lymphomagenesis
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p53 in breast cancer: mutation and countermeasures
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Natural killer cells limit the clearance of senescent lung adenocarcinoma cells
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Suppression of human tumor cell proliferation by Smurf2‐induced senescence
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p53-intact cancers escape tumor suppression through loss of long noncoding RNA Dino
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E6AP is required for replicative and oncogene-induced senescence in mouse embryo fibroblasts
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“5 In order to analyze the effects of TAF10 absence on development, we performed a tamoxifen-inducible ubiquitous deletion of Taf10 using the R26 line (Ventura et al., 2007).”
The Anti-Breast Cancer Effects of Green-Synthesized Zinc Oxide Nanoparticles Using Carob Extracts
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Metadata
- Authors
- Ventura, A., Kirsch, D. G., McLaughlin, M. E., Tuveson, D. A., Grimm, J., Lintault, L., Newman, J., Reczek, E. E., Weissleder, R., & Jacks, T.
- Affiliations
- Massachusetts Institute of Technology (US)
- Massachusetts General Hospital (US)
- Harvard University (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Jacks, Tyler
- ORCID
- Venue
- Nature
- Published
- 2007-01-24
- Volume
- 445
- Issue
- 7128
- Pages
- 661-665
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2154799239
- Cited by
- 1,820
- References
- 31
- Citations by year
- 2026: 44 · 2025: 78 · 2024: 83 · 2023: 77 · 2022: 96 · 2021: 94 · 2020: 78 · 2019: 83 · 2018: 80 · 2017: 100 · 2016: 95 · 2015: 99 · 2014: 113 · 2013: 108 · 2012: 104
- FWCI
- 60.89
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- p53 reactivation, tumor regression, tumor suppressor, cellular senescence, innate immune response, tumor clearance, oncogene addiction, sarcoma, apoptosis
- MeSH terms
- Alleles, Animals, Cell Division, Disease Models, Animal, Humans, Lymphoma, Neoplasms, Organ Specificity, Sarcoma, Tumor Suppressor Protein p53, Cellular Senescence, Apoptosis, Mice
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