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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BackgroundTranscription factors: Time to deliver
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“These results are consistent with previous studies showing an increase in p53 target genes by CP31398, as well as in p53 reporter gene expression in cancer cells (11, 13, 29, 39).”
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Insights from In Vivo Studies of Cellular Senescence
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“The ability of p53 to prevent the expansion of cells with potentially pre-neoplastic alterations has been elegantly described, as restoration of p53 expression in p53-null sarcomas induced senescence and suppressed tumorigenesis [7,8].”
BackgroundTransgenic expression of cyclooxygenase-2 (COX2) causes premature aging phenotypes in mice
Kim, J., Vaish, V., Feng, M., Field, K., Chatzistamou, I., & Shim, M. (2016) · Aging · doi:10.18632/aging.101060 · Cited by 41
Amino acids-Rab1A-mTORC1 signaling controls whole-body glucose homeostasis
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“Rab1AFlox/Flox mice were then mated with ROSACreERT2/ERT2 (Ventura et al., 2007) to generate ROSA-CreERT2/+; Rab1AFlox/+ mice.”
MethodPromising New Tools for Targeting p53 Mutant Cancers: Humoral and Cell-Based Immunotherapies
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“of p53 function is considered an important issue in cancer therapy [6,7,8].”
BackgroundChallenges and advances in mouse modeling for human pancreatic tumorigenesis and metastasis
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p53-mediated apoptosis prevents the accumulation of progenitor B cells and B-cell tumors
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BackgroundTherapeutic targeting of the p53 pathway in cancer stem cells
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“Indeed, previous studies showed that acute restoration of p53 in spontaneously arising sarcomas andmutantHrasV12Ddrivenmurine liver carcinomas resulted in tumor regression in the absence of apoptosis, but with the appearance of markers of senescence (Martins et al., 2006; Ventura et al., 2007).”
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“…mouse lines were used: Pdx1-tTA 41 , tetO-HIST1HBJ/GFP(tetO-H2B-GFP) 42 , Hnf1btm(CreER) (Hnf1b CreER ) 17 , Gt (ROSA) 26Sortm4(ACTB-tdTomato,-EGFP)Luo/J ( mT/mG ) 24 , Ptf1aCreERTM ( Ptf1a CreER ) 16 , Tg(Hes1-EGFP) 1H ri ( Hes1-eGFP ) 43 , Gt(ROSA)26Sor tm1(cre/ERT2)Tyj /J ( Rosa26 CreER ) 23 .”
BackgroundSpred1 Safeguards Hematopoietic Homeostasis against Diet-Induced Systemic Stress
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A calcium transport mechanism for atrial fibrillation in Tbx5-mutant mice
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“Generation of mice The Tbx5, Pln and Rosa26 lines have all been previously described and were kept in a mixed genetic background (Luo et al., 1994; Bruneau et al., 2001; Ventura et al., 2007).”
BackgroundAssociation of p53 with Neurodegeneration in Parkinson’s Disease
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“…R26CreERT2 mice that carry a Cre recombinase fused to the mutant estrogen receptor T2 allele targeted to the ubiquitously expressed ROSA 26 locus (Ventura et al., 2007) to generate p53 homozygous mutant mice carrying Tacc3-silent/null and CreERT2 alleles (p53 / ; Tacc3S/D; CreERT2) and p53…”
InfluentialHuman MutL-complexes monitor homologous recombination independently of mismatch repair
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“D o no t d is tri bu te . www.landesbioscience.com Cell Cycle 2469 PAPer tyPe rePOrt Ventura et al.9 showed that lymphoma cells underwent apoptosis and sarcomas displayed replicative senescence, while Xue et al.10 found that liver tumor cells cleared rapidly, with apparent activation of the innate immune system.”
BackgroundCritical requirement of VEGF-C in transition to fetal erythropoiesis
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“Recently, two independent studies on transgenic mice demonstrated that restoration of p53 activity enables tumor regression in vivo [6,7]. p53 reactivation is especially promising in regression of advanced stage cancers [8,9].”
BackgroundHigh glucose dephosphorylates serine 46 and inhibits p53 apoptotic activity
Garufi, A., & D’Orazi, G. (2014) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-014-0079-4 · Cited by 40
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Deng, L., He, K., Pan, Y., Wang, H., Luo, Y., & Xia, Q. (2021) · International Journal of Medical Sciences · doi:10.7150/ijms.56003 · Cited by 36
“These pathways promote cellular senescence by activating genes that inhibit cell cycle progression and promote senescence [19-22].”
BackgroundHematopoiesis under telomere attrition at the single-cell resolution
Thongon, N., Ma, F., Santoni, A., Marchesini, M., Fiorini, E., Rose, A. M., Ademà, V., Gañán‐Gómez, I., Groarke, E. M., Gutierrez‐Rodrigues, F., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-27206-7 · Cited by 42
Senescence of Tumor Cells in Anticancer Therapy—Beneficial and Detrimental Effects
Piskorz, W. M., & Cechowska‐Pasko, M. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms231911082 · Cited by 39
Baharara, J., Hosseini, N., & Ramezani, T. (2015) · Cytotechnology · doi:10.1007/s10616-015-9900-y · Cited by 39
“In addition, P53 protein affects enhanced transcription of pro-apoptotic Bax directly while it decreased transcription of antiapoptotic Bcl-2 proteins (Ventura et al. 2007).”
BackgroundKontoghiorghes, G. J., Efstathiou, A., Ioannou-Loucaides, S., & Kolnagou, A. (2008) · Hemoglobin · doi:10.1080/03630260701727119 · Cited by 39
A Theoretical Exploration of Birhythmicity in the p53-Mdm2 Network
Abou-Jaoudé, W., Madalena Chaves, A., & Gouzé, J. (2011) · PLoS ONE · doi:10.1371/journal.pone.0017075 · Cited by 38
“Recent experiments performed in the p53-Mdm2 network, one of the key protein module involved in the control of proliferation of abnormal cells in mammals [8,9,10], reported two oscillatory regimes of p53 and Mdm2 in irradiated cells [11]: a low-frequency oscillatory regime at low irradiation dose with a period of abou…”
BackgroundMDM2 and MDMX in Cancer and Development
Marine, J. (2011) · Current topics in developmental biology/Current Topics in Developmental Biology · doi:10.1016/b978-0-12-380916-2.00003-6 · Cited by 39
Controversial aspects of oncogene-induced senescence
Bianchi, A., & Nikiforov, M. A. (2012) · Cell Cycle · doi:10.4161/cc.22589 · Cited by 39
“Accordingly, studies performed in transgenic mice demonstrated an active role of p53 and p16 in the implementation of OIS in murine models.(34,46-49) In normal human cells, however, the role of these tumor suppressors in senescence induced by activated RAS appears to be less straightforward.”
BackgroundThe Msx1 Homeoprotein Recruits G9a Methyltransferase to Repressed Target Genes in Myoblast Cells
Wang, J., & Abate-Shen, C. T. (2012) · PLoS ONE · doi:10.1371/journal.pone.0037647 · Cited by 38
“The Msx1 mutant were performed using a compound Msx1; Msx2 conditional allele [40] crossed to a ubiquitously-expressed tamoxifen-inducible Rosa26 allele [41] to generate mice of the genotype Rosa26; Msx1; Msx2.”
MethodRetractedHallmarks for senescence in carcinogenesis: novel signaling players
Caino, M. C., Meshki, J., & Kazanietz, M. G. (2009) · APOPTOSIS · doi:10.1007/s10495-009-0316-z · Cited by 40
Switching on p53: an essential role for protein phosphorylation?
Loughery, J., & Meek, D. W. (2013) · Biodiscovery · doi:10.7750/biodiscovery.2013.8.1 · Cited by 39
“Correspondingly, restoring wild type p53 function in animal models can regress cancer development and significantly extend periods of survival [26-28].”
Wig1 prevents cellular senescence by regulating p21 mRNA decay through control of RISC recruitment
Kim, B. C., Lee, H. C., Lee, J., Choi, C., Kim, D.-K., Lee, J. C., Ko, Y., & Lee, J. (2012) · The EMBO Journal · doi:10.1038/emboj.2012.286 · Cited by 41
“Cellular senescence, however, has recently begun to be described as a tumour suppression mechanism as potent as apoptosis (Ventura et al , 2007; Wu et al , 2007; Byun et al , 2009; Lee et al , 2011).”
A DR4:tBID axis drives the p53 apoptotic response by promoting oligomerization of poised BAX
Henry, R. E., Andrysík, Z., París, R., Galbraith, M. D., & Espinosa, J. M. (2012) · The EMBO Journal · doi:10.1038/emboj.2011.498 · Cited by 40
“EMBO open”
Dell’Aringa, M., & Reinhardt, R. L. (2018) · Mucosal Immunology · doi:10.1038/s41385-018-0012-9 · Cited by 38
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“It has been proven by different research groups that restoration of p53 function leads to marked regression of established lymphomas, sarcomas, and liver carcinomas in vivo (37).”
BackgroundCellular senescence signaling in cancer: A novel therapeutic target to combat human malignancies
Fakhri, S., Moradi, S. Z., DeLiberto, L. K., & Bishayee, A. (2022) · Biochemical Pharmacology · doi:10.1016/j.bcp.2022.114989 · Cited by 39
p73 as a Pharmaceutical Target for Cancer Therapy
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“it It is now established that pharmacological manipulation aimed at restoring the levels/functions of the p53 protein can induce tumor regression in vivo [15-18].”
BackgroundModeling therapy resistance in genetically engineered mouse cancer models
Rottenberg, S., & Jonkers, J. (2008) · Drug Resistance Updates · doi:10.1016/j.drup.2007.11.002 · Cited by 38
Pharmacological Activation of p53 in Cancer Cells
Athar, M., Elmets, C. A., & Kopelovich, L. (2011) · Current Pharmaceutical Design · doi:10.2174/138161211795222595 · Cited by 40
MNK, EIF4E and targeting translation for therapy
Silva, R. L. A., & Wendel, H. (2008) · Cell Cycle · doi:10.4161/cc.7.5.5486 · Cited by 38
p53 Aerosol Formulation with Low Toxicity and High Efficiency for Early Lung Cancer Treatment
Zou, Y., Tornos, C. S., Qiu, X., Lia, M., & Perez-Soler, R. (2007) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-07-0395 · Cited by 38
Senescence and pre-malignancy: How do tumors progress?
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Dynamics of BMP signaling in limb bud mesenchyme and polydactyly
Norrie, J. L., Lewandowski, J. P., Bouldin, C. M., Amarnath, S., Li, Q., Vokes, M. S., Ehrlich, L. I. R., Harfe, B. D., & Vokes, S. A. (2014) · Developmental Biology · doi:10.1016/j.ydbio.2014.07.003 · Cited by 37
“5 but additional experiments using the ubiquitous RosaCre-ERT2 (Ventura et al., 2007), which is expressed ubiquitously upon tamoxifen activation, indicated that RosaCre-ERT2/Gremlin”
BackgroundMyc, Cdk2 and cellular senescence: Old players, new game
Campaner, S., Doni, M., Verrecchia, A., Fagà, G., Bianchi, L., & Amati, B. B. (2010) · Cell Cycle · doi:10.4161/cc.9.18.13049 · Cited by 39
Sp1 regulates Raf/MEK/ERK-induced p21CIP1 transcription in TP53-mutated cancer cells
Karkhanis, M. S., & Park, J. (2015) · Cellular Signalling · doi:10.1016/j.cellsig.2015.01.005 · Cited by 38
Programmed cell senescence: role of IL-6 in the pituitary
Sapochnik, M., Fuertes, M., & ARZT, E. S. (2017) · Journal of Molecular Endocrinology · doi:10.1530/jme-17-0026 · Cited by 42
Combined allelic dosage of Nfia and Nfib regulates cortical development
Bunt, J., Osinski, J. M., Lim, J. W. C., Vidovic, D., Ye, Y., Zalucki, O. H., O’Connor, T. R., Harris, L., Gronostajski, R. M., Richards, L. J., et al. (2017) · Brain and Neuroscience Advances · doi:10.1177/2398212817739433 · Cited by 33
“Double heterozygous Nfia;Nfib knockout embryos have similar brain defects to those of single homozygous knockout mice To test whether the total number of Nfi alleles modulates cortical development, we crossed Nfia knockout (Das Neves et al., 1999) with Nfib conditional (Hsu et al., 2011); R26-CreERT (Ventura et al., 2…”
BackgroundInfluentialMutant p53R270H drives altered metabolism and increased invasion in pancreatic ductal adenocarcinoma
Schofield, H. K., Zeller, J., Espinoza, C. E., Halbrook, C. J., Vecchio, A. D., Magnuson, B., Fabo, T., Daylan, A. E. C., Kovalenko, I., Lee, H., et al. (2018) · JCI Insight · doi:10.1172/jci.insight.97422 · Cited by 38
CHEK1 coordinates DNA damage signaling and meiotic progression in the male germline of mice
Abe, H., Alavattam, K. G., Kato, Y., Castrillón, D. H., Pang, Q., Andreassen, P. R., & Namekawa, S. H. (2018) · Human Molecular Genetics · doi:10.1093/hmg/ddy022 · Cited by 33
Induction and transmission of oncogene-induced senescence
Rattanavirotkul, N., Kirschner, K., & Chandra, T. (2020) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-020-03638-0 · Cited by 41
Mitochondrial apoptotic priming is a key determinant of cell fate upon p53 restoration
Rivera, F. J. S., Ryan, J. A., Soto‐Feliciano, Y. M., Beytagh, M. C., Xuan, L. L., Feldser, D. M., Hemann, M. T., Zamudio, J. R., Dimitrova, N., Letai, A. G., et al. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2019740118 · Cited by 36
“These mice harbor a Kras allele, which leads to spontaneous expression of the Kras oncogene (14), as well as two LSL p53 alleles (9), which prevent expression of endogenous p53 and phenocopy p53-deficient mice.”
BackgroundSelf-citationDying to Survive—The p53 Paradox
Lees, A., Sessler, T., & McDade, S. S. (2021) · Cancers · doi:10.3390/cancers13133257 · Cited by 38
Molecular Targeted Therapy and Immunotherapy for Myelodysplastic Syndrome
Lee, P., Yim, R., Yung, Y., Chu, H.-T., Yip, P.-K., & Gill, H. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms221910232 · Cited by 40
Novel Perspectives on p53 Function in Neural Stem Cells and Brain Tumors
Hede, S., Nazarenko, I., Nistér, M., & Lindström, M. S. (2010) · Journal of Oncology · doi:10.1155/2011/852970 · Cited by 40
“Tumors with dysfunctional or no p53 have been shown to undergo apoptosis or senescence in vivo upon functional restoration of p53 [150, 151].”
BackgroundInduction of p53 Renders ATM-Deficient Mice Refractory to Hepatocarcinogenesis
Teoh, N., Pyakurel, P., Dan, Y. Y., Swisshelm, K. L., Hou, J. Y., Mitchell, C., Fausto, N., Gu, Y., & Farrell, G. C. (2009) · Gastroenterology · doi:10.1053/j.gastro.2009.11.008 · Cited by 39
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“Reactivation of p53 in tumors has been shown to elicit robust tumor regression, mediated by senescence induction ( 43 , 44 ), and compounds that enhance p53 activity are currently in phase 2 clinical trials to treat cancer (NCT02965950).”
Tumor Suppression by p53: Fall of the Triumvirate?
Hock, A. K., & Vousden, K. H. (2012) · Cell · doi:10.1016/j.cell.2012.05.024 · Cited by 36
“Finally, reactivation of p53 in established tumors results in tumor regression that is accompanied by either apoptosis or senescence, depending on the tumor type (Ventura et al., 2007).”
BackgroundLaine, A., & Westermarck, J. K. (2014) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-13-1942 · Cited by 41
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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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