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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“Restoration of p53 functions in lymphomas, sarcomas, and liver carcinomas leads to the features of cellular senescence and tumor regression [126,127], which is mainly mediated by the chronic inflammation and innate immune system triggered by senescent stromal cells [127].”
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“…GEMMs with reversible inactivation of p53 have shown that restoration of p53 leads to rapid regression of established tumors (Martins et al , 2006; Ventura et al , 2007; Xue et al , 2007), providing strong rationale for designing anti-cancer drugs that restore p53 function by inhibiting MDM2…”
Reciprocal regulation of p53 and malic enzymes modulates metabolism and senescence
Jiang, P., Du, W., Mancuso, A., Wellen, K. E., & Yang, X. (2013) · Nature · doi:10.1038/nature11776 · Cited by 491
The Cytokine GM-CSF Drives the Inflammatory Signature of CCR2+ Monocytes and Licenses Autoimmunity
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Development and plasticity of meningeal lymphatic vessels
Antila, S., Karaman, S., Nurmi, H. J., Airavaara, M., Voutilainen, M. H., Mathivet, T., Chilov, D., Li, Z., Koppinen, T. K., Park, J., et al. (2017) · The Journal of Experimental Medicine · doi:10.1084/jem.20170391 · Cited by 469
“…Vegfd−/− (C57BL/6J; Baldwin et al., 2005), Vegfcflox/flox (C57BL/6J; Aspelund et al., 2014), Vegfr3flox/flox (C57BL/6J; Haiko et al., 2008), Rosa26-CreERT2 (C57BL/6J; Ventura et al., 2007), and BAC Vegfr3 :YFP (C57BL/6J; Calvo et al., 2011) transgenic mouse lines have been previously described.”
BackgroundInfluentialTumours with PI3K activation are resistant to dietary restriction
Kalaany, N. Y., & Sabatini, D. M. (2009) · Nature · doi:10.1038/nature07782 · Cited by 468
The p53 network: cellular and systemic DNA damage responses in aging and Cancer
Reinhardt, H. C., & Schumacher, B. (2012) · Trends in Genetics · doi:10.1016/j.tig.2011.12.002 · Cited by 458
Inside and out: the activities of senescence in cancer
Pérez-Mancera, P. A., Young, A. R. J., & Narita, M. (2014) · Nature Reviews Cancer · doi:10.1038/nrc3773 · Cited by 462
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“The p53 protein is a zinc-binding protein containing several reactive cysteines and its key biochemical property, sequence-speciWc DNA binding, is dependent upon metal and redox regulation in vitro (Ventura et al. 2007).”
BackgroundDimitrova, N., Zamudio, J. R., Jong, R. M., Soukup, D., Resnick, R., Sarma, K., Ward, A. J., Raj, A., Lee, J. T., Sharp, P. A., et al. (2014) · Molecular Cell · doi:10.1016/j.molcel.2014.04.025 · Cited by 445
“Rosa26-CreERT2 (Ventura et al., 2007) and p21 mice (The Jackson Laboratory, stock number 003263) have previously been described .”
BackgroundSelf-citationGodár, S., Ince, T. A., Bell, G. W., Feldser, D. M., Donaher, J. L., Bergh, J. C. S., Liu, A. Y., Miu, K., Watnick, R. S., Reinhardt, F., et al. (2008) · Cell · doi:10.1016/j.cell.2008.06.006 · Cited by 455
“…was a consequence of genomic instability in these p53 À/À mice, we took advantage of a recently published conditional mouse model, in which p53 expression is restored in otherwise p53 null tissues of mice by administration of tamoxifen to activate the Cre recombinase (Ventura et al., 2007).”
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“C p53 pathway is not fully understood at the molecular level, it has been well established that activated p53 suppresses cancer progression, underlining why cancer cells have developed multiple mechanisms to disable p53 function (Danovi et al., 2004; Ventura et al., 2007).”
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BackgroundMethodInfluentialSelf-citationOncogene addiction: setting the stage for molecularly targeted cancer therapyPreprint
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“While translation of this concept to cancer patients remains to be realized, recent studies in transgenic mice provide proof of concept and lend validity to p53 restoration as a cancer therapeutic strategy (Martins et al. 2006; Ventura et al. 2007; Xue et al. 2007).”
BackgroundDicer1 functions as a haploinsufficient tumor suppressorPreprint
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“This has been most clearly demonstrated for the miR-17;92 cluster, whose amplification in B-cell lymphomas promotes their development, potentially through its control of B-cell differentiation (He et al. 2005; Koralov et al. 2008; Ventura et al. 2008).”
BackgroundSelf-citationPro-senescence therapy for cancer treatment
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“, and some of these have been successfully validated in vivo in mice, including the basic helix–loop–helix transcription factor BHLHE40 (also known as DEC1) and decoy receptor 2 (DCR2; also known as TNFRSF10D”
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“…by activation of p53/p21 and p16/Rb tumor sup pressor pathways, which promote senescence by transactivating genes that arrest cell cycle progression and promote the senescent state (Serrano et al., 1997; Narita et al., 2003; Braig et al., 2005; Michaloglou et al., 2005; Ventura et al., 2007).”
Polylox barcoding reveals haematopoietic stem cell fates realized in vivo
Pei, W., Feyerabend, T. B., Rößler, J., Wang, X., Postrach, D., Busch, K., Rode, I., Klapproth, K., Dietlein, N., Quedenau, C., et al. (2017) · Nature · doi:10.1038/nature23653 · Cited by 440
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“This notion that p53 is able to activate different checkpoint programmes 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, whereas inhibition of sarcomas requires activation of a cellu…”
BackgroundCellular senescence is an important mechanism of tumor regression upon c-Myc inactivation
Wu, C.-H., van Riggelen, J., Yetil, A., Fan, A. C., Bachireddy, P., & Felsher, D. W. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0701953104 · Cited by 417
Oncogenic stress sensed by the immune system: role of natural killer cell receptors
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“Activated p19ARF and the DNA damage response can each independently induce the expression of p53 and other mediators that arrest the cell cycle and can lead to cell senescence ( Box 3 ) or apoptosis when persistently activate”
BackgroundSkp2 targeting suppresses tumorigenesis by Arf-p53-independent cellular senescence
Lin, H.-K., Chen, Z., Wang, G., Nardella, C., Lee, S.-W., Chan, C.-H., Yang, W.-L., Wang, J., Egia, A., Nakayama, K. I., et al. (2010) · Nature · doi:10.1038/nature08815 · Cited by 400
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“In tumors with wild type p53, activation of p53 to induce apoptosis can be achieved by blocking Mdm2 or Mdm4 binding to p53 (Martins et al., 2006; Shchors et al., 2013; Ventura et al., 2007; Wang et al., 2011; Xue et al., 2007).”
Many roads lead to oncogene-induced senescence
Courtois-Cox, S., Jones, S. L., & Cichowski, K. (2008) · Oncogene · doi:10.1038/sj.onc.1210950 · Cited by 397
“However, several studies have now established a more causal role for senescence in this process (Sarkisian et al., 2007; Ventura et al., 2007; Xue et al., 2007).”
BackgroundResultStructural basis for high-affinity peptide inhibition of p53 interactions with MDM2 and MDMX
Pazgier, M., Liu, M., Zou, G., Yuan, W., Li, C., Li, C., Li, J., Monbo, J., Zella, D., Tarasov, S. G., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0900947106 · Cited by 391
The Lkb1 metabolic sensor maintains haematopoietic stem cell survival
Gurumurthy, S., Xie, S. Z.-J., Alagesan, B., Kim, J., Yusuf, R. Z., Sáez, B., Tzatsos, A., Ozsolak, F., Milos, P. M., Ferrari, F., et al. (2010) · Nature · doi:10.1038/nature09572 · Cited by 407
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“Indeed, exciting recent findings have shown that reactivation of p53 expression in mouse models induces tumor regression (Martins et al., 2006; Ventura et al., 2007; Xue et al., 2007).”
BackgroundShaping Genetic Alterations in Human Cancer: The p53 Mutation Paradigm
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“…based on p53 reactivation in p53-deficient tumors can lead either to potent apoptosis or cellular senescence, depending on the type of tumor, should encourage us to undertake more global analysis of the p53 status in tumor cells (Martins et al., 2006; Ventura et al., 2007; Xue et al., 2007).”
BackgroundInfluentialMutant p53 as a target for cancer treatment
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Curcumin as an Alternative Epigenetic Modulator: Mechanism of Action and Potential Effects
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Mdm2-mediated ubiquitylation: p53 and beyond
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The Tumor Suppressor p53: From Structures to Drug DiscoveryPreprint
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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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