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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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“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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“Conversely, restoration of p53 expression can promote apoptosis, tumor regression and clearance in vivo [63, 64].”
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Gene regulation and tumor suppression by the bromodomain-containing protein BRD7
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“Underscoring the therapeutic potential of this pathway, it has been demonstrated that reactivation of p53 in murine tumors causes cellular senescence and associated tumor regression.(8,9) Indeed, DNAdamaging chemotherapeutic agents can induce senescence in cancer cells, which contributes to the anti-tumor effect of th…”
BackgroundIgf2 pathway dependency of the Trp53 developmental and tumour phenotypes
Haley, V., Barnes, D., Sandovici, I., Constância, M., Graham, C. F., Pezzella, F., Bühnemann, C., Carter, E. J., & Hassan, A. B. (2012) · EMBO Molecular Medicine · doi:10.1002/emmm.201101105 · Cited by 30
“It has been observed that anti-tumour effects can occur following re-introduction of a WT p53 allele in p53 null tumours (Martins et al, 2006; Ventura et al, 2007; Xue et al, 2007).”
Pluripotent human stem cell lines: what we can learn about cancer initiation
Werbowetski‐Ogilvie, T. E., & Bhatia, M. (2008) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2008.06.005 · Cited by 31
MDM2 inhibition in the treatment of glioblastoma: From concept to clinical investigation
Pellot Ortiz, K. I., Rechberger, J. S., Nonnenbroich, L. F., Daniels, D. J., & Sarkaria, J. N. (2023) · Biomedicines · doi:10.3390/biomedicines11071879 · Cited by 30
Therapeutic Efficacy of p53 Restoration in Mdm2 -Overexpressing Tumors
Li, Q., Zhang, Y., El-Naggar, A. K., Xiong, S., Yang, P., Jackson, J. G., Chau, G., & Lozano, G. (2014) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-14-0089 · Cited by 30
“org Mol Cancer Res; 12(6) June 2014 905”
BackgroundInfluentialConradt, L., Henrich, A., Wirth, M., Reichert, M., Lesina, M., Algül, H., Schmid, R. M., Krämer, O. H., Saur, D., & Schneider, G. (2013) · International Journal of Cancer · doi:10.1002/ijc.27916 · Cited by 30
Lineage plasticity and histological transformation: tumor histology as a spectrum
Li, X., Gardner, E. E., Molina‐Pinelo, S., Wilhelm, C., Mu, P., & Quintanal-Villalonga, À. (2025) · Cell Research · doi:10.1038/s41422-025-01180-x · Cited by 33
“99,138 139 – 141 To the best of our knowledge, most studies describing model systems to study histologic transformation have failed to observe fully differentiated NE transformation outside of a host animal or patient, and the reason for this remains an open question.”
Stochastic and Deterministic Models of Cellular p53 Regulation
Leenders, G. B., & Tuszyński, J. A. (2013) · Frontiers in Oncology · doi:10.3389/fonc.2013.00064 · Cited by 28
“Furthermore, it has been demonstrated that restoration of p53 function can cause tumors to regress in vivo (Ventura et al., 2007).”
BackgroundYan, H., Chen, X., Li, Y., Fan, L., Tai, Y., Zhou, Y., Chen, Y., Qi, X., Huang, R., & Ren, J. (2019) · Europe PMC (PubMed Central) · Cited by 30
Follow the Mutations: Toward Class-Specific, Small-Molecule Reactivation of p53
Loh, S. N. (2020) · Biomolecules · doi:10.3390/biom10020303 · Cited by 30
Zhao, M., Wang, Y., Zhao, Y., He, S., Zhao, R., Song, Y., Cheng, J. Q., Gong, Y., Xie, J., Wang, Y., et al. (2020) · Aging · doi:10.18632/aging.103984 · Cited by 30
“This was consistent with the findings of previous studies, which demonstrated that the restoration of p53 in solid organ tumors primarily caused cell senescence than apoptosis [50, 51].”
ResultSiemer, S., Fauth, T., Scholz, P., Al-Zamel, Y., Khamis, A., Gül, D., Freudelsperger, L., Wollenberg, B., Becker, S., Stauber, R. H., et al. (2021) · Cancers · doi:10.3390/cancers13194831 · Cited by 30
PLK4 drives centriole amplification and apical surface area expansion in multiciliated cells
LoMastro, G. M., Drown, C. G., Maryniak, A. L., Jewett, C. E., Strong, M. A., & Holland, A. J. (2022) · eLife · doi:10.7554/elife.80643 · Cited by 31
Roles of H19/miR-29a-3p/COL1A1 axis in COE-induced lung cancer
Zhang, H., Li, X., Jia, M., Ji, J., Wu, Z., Chen, X., Yu, D., Zheng, Y., & Zhao, Y. (2022) · Environmental Pollution · doi:10.1016/j.envpol.2022.120194 · Cited by 30
AGO2 silences mobile transposons in the nucleus of quiescent cells
Sala, L., Kumar, M., Prajapat, M. K., Chandrasekhar, S., Cosby, R. L., Rocca, G. L., Macfarlan, T. S., Awasthi, P., Chari, R., Kruhlak, M. J., et al. (2023) · Nature Structural & Molecular Biology · doi:10.1038/s41594-023-01151-z · Cited by 30
Controlling the Mdm2-Mdmx-p53 Circuit
Waning, D. L., Lehman, J. A., Batuello, C. N., & Mayo, L. D. (2010) · Pharmaceuticals · doi:10.3390/ph3051576 · Cited by 30
“For tumors harboring wild-type p53, re-activating p53 in established tumor cells represents an effective intervention scheme [91,92].”
BackgroundRao, C. V., Steele, V. E., Swamy, M. V., Patlolla, J. M. R., Guruswamy, S., & Kopelovich, L. (2009) · Cancer Research · doi:10.1158/0008-5472.can-09-1377 · Cited by 31
Lü, X., Agasti, S. S., Vinegoni, C., Waterman, P. G., DePinho, R. A., & Weissleder, R. (2012) · Bioconjugate Chemistry · doi:10.1021/bc300319c · Cited by 30
Self-citationInsulin receptor-independent upregulation of cellular glucose uptake
Krishnapuram, R., Kirk-Ballard, H., Dhurandhar, E. J., Dubuisson, O. S., Messier, V., RABASA-LHORET, R. P. R., Hegde, V. K., Aggarwal, S., & Dhurandhar, N. V. (2012) · International Journal of Obesity · doi:10.1038/ijo.2012.6 · Cited by 30
“Deficiency of p53 tumor suppressor gene increases susceptibility to tumor formation(46), whereas the restoration of p53 regresses tumors(47).”
Targeted-simultaneous expression of Gas1 and p53 using a bicistronic adenoviral vector in gliomas
Benítez, J. A., Arregui, L., Vergara, P., & Segovia, J. (2007) · Cancer Gene Therapy · doi:10.1038/sj.cgt.7701076 · Cited by 30
DUSP 16 ablation arrests the cell cycle and induces cellular senescence
Zhang, H., Zheng, H., Mu, W., He, Z., Yang, B., Ji, Y., & Hui, L. (2015) · FEBS Journal · doi:10.1111/febs.13518 · Cited by 31
Yuen, T. Y., Brown, C. J., Xue, Y., Tan, Y. S., Ferrer‐Gago, F. J., Lee, X. C., Neo, J. Y., Thean, D., Kaan, H. Y. K., Partridge, A. W., et al. (2019) · Chemical Science · doi:10.1039/c9sc01456j · Cited by 30
Accumulation of senescent cells in the stroma of aged mouse ovary
Maruyama, N., FUKUNAGA, I., Tomoaki, K. O. G. O., Endo, T., Fujii, W., Kanai‐Azuma, M., Naito, K., & Sugiura, K. (2023) · Journal of Reproduction and Development · doi:10.1262/jrd.2023-021 · Cited by 31
“In fact, senescent tumor cells are observed in the pre-malignant stages of tumorigenesis [12–15] and are cleared by immune cells, such as macrophages, to ensure tumor regression [16, 17].”
BackgroundGaud, G., Achar, S. R., Bourassa, F. X. P., Davies, J., Hatzihristidis, T., Choi, S., Kondo, T., Gossa, S., Lee, J., Juneau, P. L., et al. (2023) · Nature Immunology · doi:10.1038/s41590-023-01663-2 · Cited by 32
“…chain was or could be induced in mature postselection T cells using either (1) Ert2-Cre where the 6Y to 6F switch could be induced by tamoxifen 33 , (2) dLck-Cre , where the 6Y to 6F switch occurs in CD4 + CD8 − and CD4 − CD8 + thymocytes after positive selection 34 or (3) OX40-Cre , where…”
MethodSnyder, J. C., Rochelle, L. K., Ray, C., Pack, T. F., Bock, C. B., Lubkov, V., Lyerly, H. K., Waggoner, A. S., Barak, L. S., & Caron, M. G. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.756635 · Cited by 27
Simmons, A. B., Bloomsburg, S., Sukeena, J. M., Miller, C. J., Ortega-Burgos, Y., Borghuis, B. G., & Fuerst, P. G. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1713548114 · Cited by 31
“We used two different transgenic mouse lines manipulating Dscam: (i) Dscam and (ii) Dscam; one Cre-dependent reporter mouse: Gt(ROSA)26Sortm9(CAG-tdTomato)Hze (referred to as Ai9; The Jackson Laboratory, stock no: 007909) (96); three Cre recombinaseexpressing transgenic mouse lines: (i) Tg(Htr2a-cre)KM207Gsat (referre…”
MethodIDH1 Arg-132 mutant promotes tumor formation through down-regulating p53
Jiang, B., Zhao, W., Shi, M., Zhang, J., Chen, A., Ma, H., Suleman, M., Lin, F., Zhou, L., Wang, J., et al. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.ra117.001385 · Cited by 29
“The notion that p53 function has to be disrupted for tumor progression is supported by previous studies showing that restoring p53 function is sufficient to cause regression of several types of tumors in mice (28, 29).”
BackgroundGollner, A., Weinstabl, H., Fuchs, J. E., Rudolph, D., Garavel, G., Hofbauer, K. S., Karolyi‐Oezguer, J., Gmaschitz, G., Hela, W., Kerres, N., et al. (2018) · ChemMedChem · doi:10.1002/cmdc.201800617 · Cited by 28
BACE1 partial deletion induces synaptic plasticity deficit in adult mice
Lombardo, S., Chiacchiaretta, M., Tarr, A. J., Kim, W., Cao, T., Sigal, G., Rosahl, T. W., Xia, W., Haydon, P. G., Kennedy, M. E., et al. (2019) · Scientific Reports · doi:10.1038/s41598-019-56329-7 · Cited by 30
Discovery of compounds that reactivate p53 mutants in vitro and in vivo
Durairaj, G., Demir, Ö., Lim, B., Baronio, R., Tifrea, D. F., Hall, L., DeForest, J. C., Lauinger, L., Fallatah, M. M. J., Yu, C., et al. (2022) · Cell chemical biology · doi:10.1016/j.chembiol.2022.07.003 · Cited by 31
Wang, H., Lu, J. L., Stevens, T., Roberts, A., Mandel, J. A., Avula, R., Ma, B., Wu, Y. L., Wang, J., Land, C. V., et al. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.112830 · Cited by 28
Relationship between Obesity, Gut Microbiome and Hepatocellular Carcinoma Development
Hara, E. (2015) · Digestive Diseases · doi:10.1159/000371679 · Cited by 30
van Miltenburg, M. H., & Jonkers, J. (2012) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2012.01.004 · Cited by 32
“p53 Several groups investigated the role of p53 loss-of-function in tumor maintenance by using GEMMs with reversible p53 inactivation and showed that restoration of endogenous p53 activity leads to temporal regression of autochthonous lymphomas and sarcomas [20 ,21 ] and liver carcinomas [22 ].”
BackgroundMethodHornsby, P. J. (2009) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-009-0723-6 · Cited by 29
“Possibly the most significant recent discovery is the demonstration that, in both cell culture models and tissues in vivo, senescent cells are a target for elimination by the innate immune system, particularly, natural killer (NK) cells [38, 59, 73, 77 , 85].”
BackgroundPetri, B., Speel, E. M., Korpershoek, E., Claessen, S. M. H., van Nederveen, F. H., Giesen, V., Dannenberg, H., van der Harst, E., Dinjens, W. N. M., & de Krijger, R. R. (2008) · Modern Pathology · doi:10.1038/modpathol.3801013 · Cited by 29
Insights into Wild-Type and Mutant p53 Functions Provided by Genetically Engineered Mice
Donehower, L. A. (2014) · Human Mutation · doi:10.1002/humu.22507 · Cited by 30
“P53 activation resulted in regression of both lymphomas and sarcomas, with the major mechanisms of regression being apoptosis in lymphomas and senescence in sarcomas [Ventura et al., 2007].”
BackgroundMethodModulation of immune responses by the tumor suppressor p53
Lowe, J. M., Shatz, M., Resnick, M. A., & Menéndez, D. (2013) · Biodiscovery · doi:10.7750/biodiscovery.2013.8.2 · Cited by 30
“For example, DNA damage can trigger p53 responses that help orchestrate clearance of damaged cells via the innate immune system [6, 7], which can influence tumor suppression.”
BackgroundMingote, S., Masson, J., Gellman, C., Thomsen, G. M., Lin, C., Merker, R. J., Gaisler‐Salomon, I., Wang, Y., Ernst, R., Hen, R., et al. (2016) · Frontiers in Systems Neuroscience · doi:10.3389/fnsys.2015.00165 · Cited by 32
“Other ubiquitous inducible promoters should be essayed, such as ROSAERT2cre (Ventura et al., 2007) and UBCERT2cre (Ruzankina et al., 2007).”
BackgroundCutting-Edge Apoptosis-Based Therapeutics
Fischer, U., Janssen, K., & Schulze‐Osthoff, K. (2007) · BioDrugs · doi:10.2165/00063030-200721050-00001 · Cited by 29
p53 mutation and deletion contribute to tumor immune evasion
Liu, S. M., Liu, T., Jiang, J., Guo, H., & Yang, R. L. (2023) · Frontiers in Genetics · doi:10.3389/fgene.2023.1088455 · Cited by 31
“Restoring the function or expression of p53 has been proved to inhibit tumor progression and even reduce tumor size in both in vivo and in vitro experiments (Ventura et al., 2007; Guinea-Viniegra et al., 2012).”
Backgroundde Assis, L. V. M., & Isoldi, M. C. (2013) · Tumor Biology · doi:10.1007/s13277-013-1210-4 · Cited by 27
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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