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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Pathologies Associated with the p53 ResponsePreprint
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“cence induction, as its inhibition leads to tumor formation while its restoration induces senescence [54,55,58,59].”
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“Results To identify the cell types and lineages in the adult dependent on RIPK1 for survival, we mated conditional Ripk1 mice to the tamoxifen-inducible Rosa26CreER transgenic mice (27) (Fig.”
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Aggarwal, M., Saxena, R., Sinclair, E., Fu, Y., Jacobs, A., Dyba, M., Wang, X., Cruz, I., Berry, D., Kallakury, B., et al. (2016) · Cell Death & Differentiation · doi:10.1038/cdd.2016.48 · Cited by 101
“The reactivation of p53 has been shown in mouse model.(28)”
BackgroundPitiyage, G. N., Slijepčević, P., Gabrani, A., Chianea, Y. G., Lim, K. P., Prime, S. S., Tilakaratne, W. M., Fortune, F., & Parkinson, E. K. (2010) · The Journal of Pathology · doi:10.1002/path.2839 · Cited by 101
Alginate/CaCO3 Hybrid Nanoparticles for Efficient Codelivery of Antitumor Gene and Drug
Zhao, D. M., Liu, C., Zhuo, R., & Cheng, S. (2012) · Molecular Pharmaceutics · doi:10.1021/mp3002123 · Cited by 100
Of the many cellular responses activated by TP53, which ones are critical for tumour suppression?
Thomas, A., Kelly, G. L., & Strasser, A. (2022) · Cell Death and Differentiation · doi:10.1038/s41418-022-00996-z · Cited by 102
“In the case of cMYC-driven lymphomas, the expression of wt TRP53 caused tumour regression through induction of apoptosis [76], but in mutant RAS driven liver cancers, cessation of tumour expansion was associated with induction of cell senescence [77, 78].”
BackgroundTran, P. T., Shroff, E. H., Burns, T. F., Thiyagarajan, S., Das, S., Zabuawala, T., Chen, J., Cho, Y., Luong, R. H., Tamayo, P., et al. (2012) · PLoS Genetics · doi:10.1371/journal.pgen.1002650 · Cited by 108
“Others have shown senescence can arise in vivo in established tumors by targeting an initiating oncogene or reconstitution of a tumor suppressor [21,64,65,66].”
Constitutive HER2 Signaling Promotes Breast Cancer Metastasis through Cellular Senescence
Angelini, P. D., Fluck, M. F. Z., Pedersen, K., Parra-Palau, J. L., Guiu, M., Morales, C. B., Vicario, R., Luque-García, A., Navalpotro, N. P., Giralt, J., et al. (2013) · Cancer Research · doi:10.1158/0008-5472.can-12-2301 · Cited by 104
Axonal organization defects in the hippocampus of adult conditional BACE1 knockout mice
Ou-Yang, M.-H., Kurz, J. E., Nomura, T., Popovic, J., Rajapaksha, T. W., Dong, H., Contractor, A., Chetkovich, D. M., Tourtellotte, W. G., & Vassar, R. (2018) · Science Translational Medicine · doi:10.1126/scitranslmed.aao5620 · Cited by 94
Peltonen, K., Colis, L. C., Liu, H., Jäämaa, S., Moore, H. M., Enbäck, J., Laakkonen, P., Vaahtokari, A., Jones, R. J., af Hällström, T. M., et al. (2010) · PLoS ONE · doi:10.1371/journal.pone.0012996 · Cited by 107
Transcriptional regulation of cellular senescence
Lanigan, F., Geraghty, J. G., & Bracken, A. P. (2011) · Oncogene · doi:10.1038/onc.2011.34 · Cited by 95
“…of p53 has been proposed as an effective therapeutic intervention, as re-induction of p53 expression in malignant tumours in mice leads to rapid tumour regression owing to the induction of cellular senescence or apoptosis, depending on the tumour type (Ventura et al., 2007; Xue et al., 2007).”
Oncogene and therapeutic target analyses in atypical fibroxanthomas and pleomorphic dermal sarcomas
Helbig, D., Ihle, M. A., Pütz, K., Tantcheva‐Poór, I., Mauch, C., Büttner, R., & Quaas, A. (2016) · Oncotarget · doi:10.18632/oncotarget.7845 · Cited by 99
Gene Therapy: The First Approved Gene-Based Medicines, Molecular Mechanisms and Clinical Indications
Räty, J. K., Pikkarainen, J. T., Wirth, T. C., & Ylä‐Herttuala, S. (2008) · Current Molecular Pharmacology · doi:10.2174/1874467210801010013 · Cited by 98
FoxM1c Counteracts Oxidative Stress-induced Senescence and Stimulates Bmi-1 Expression
Li, S. K. M., Smith, D. K., Leung, W. Y., Cheung, A. M. S., Lam, E. W. ‐., Dimri, G. P., & Yao, K. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m709604200 · Cited by 99
Transcriptional modulation induced by ionizing radiation: p53 remains a central player
Rashi‐Elkeles, S., Elkon, R., Shavit, S., Lerenthal, Y., Linhart, C., Kupershtein, A., Amariglio, N., Rechavi, G., Shamir, R., & Shiloh, Y. (2011) · Molecular Oncology · doi:10.1016/j.molonc.2011.06.004 · Cited by 95
Targeting the Oncogenic p53 Mutants in Colorectal Cancer and Other Solid Tumors
Li, H., Zhang, J., TONG, J. H. M., Chan, A. W. H., Yu, J. Q., Kang, W., & To, K. F. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20235999 · Cited by 100
Effector differentiation downstream of lineage commitment in ILC1s is driven by Hobit across tissues
Friedrich, C., Taggenbrock, R. L. R. E., Doucet-Ladevèze, R., Golda, G., Moenius, R., Arampatzi, P., Kragten, N. A. M., Kreymborg, K., de Agüero, M. G., Kastenmüller, W., et al. (2021) · Nature Immunology · doi:10.1038/s41590-021-01013-0 · Cited by 103
Wang, Z., Burigotto, M., Ghetti, S., Vaillant, F., Tan, T., Capaldo, B. D., Palmieri, M., Hirokawa, Y., Tai, L., Simpson, D. S., et al. (2023) · Cancer Discovery · doi:10.1158/2159-8290.cd-23-0402 · Cited by 108
Cell fate regulation governed by p53: Friends or reversible foes in cancer therapy
Song, B., Yang, P., & Zhang, S. (2024) · 癌症：英文版 · doi:10.1002/cac2.12520 · Cited by 103
Blocking of p53-Snail Binding, Promoted by Oncogenic K-Ras, Recovers p53 Expression and function
Lee, S.-H., Lee, S.-J., Jung, Y. S., Xu, Y., Kang, H. S., Ha, N., & Park, B.-J. (2009) · Neoplasia · doi:10.1593/neo.81006 · Cited by 100
“[7] Ventura A, Kirsch DG, McLaughlin ME, Tuveson DA, Grimm J, Lintault L,”
Backgroundc-Myc-induced transcription factor AP4 is required for host protection mediated by CD8+ T cells
Chou, C., Pinto, A. K., Curtis, J. D., Persaud, S. P., Cella, M., Lin, C., Edelson, B. T., Allen, P. M., Colonna, M., Pearce, E. L., et al. (2014) · Nature Immunology · doi:10.1038/ni.2943 · Cited by 97
The Msx1 Homeoprotein Recruits Polycomb to the Nuclear Periphery during Development
Wang, J., Kumar, R., Biggs, V. J., Lee, H., Chen, Y., Kagey, M. H., Young, R. A., & Abate-Shen, C. T. (2011) · Developmental Cell · doi:10.1016/j.devcel.2011.07.003 · Cited by 103
“, 2007) crossed with an inducible Rosa (Ventura et al., 2007).”
InfluentialJanovick, J. A., Stewart, M. D., Jacob, D., Martin, L., Deng, J. M., Stewart, C. A., Wang, Y., Cornea, A. M., Chavali, L., Lopez, S., et al. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1315194110 · Cited by 95
“There is support for this strategy in the literature (15, 16).”
BackgroundUncoupling Cancer Mutations Reveals Critical Timing of p53 Loss in Sarcomagenesis
Young, N. P., Crowley, D. G., & Jacks, T. (2011) · Cancer Research · doi:10.1158/0008-5472.can-10-4563 · Cited by 91
“To control p53 deletion, we also crossed the R26 allele, which contains a tamoxifen-inducible allele of Cre driven from the ubiquitously expressed Rosa26 locus (15).”
Self-citationPiunti, A., Rossi, A., Cerutti, A., Albert, M., Jammula, S., Scelfo, A., Cedrone, L., Fragola, G., Olsson, L., Koseki, H., et al. (2014) · Nature Communications · doi:10.1038/ncomms4649 · Cited by 93
Zeng, X., Sun, Y., Qu, W., Zhang, X., & Zhuo, R. (2010) · Biomaterials · doi:10.1016/j.biomaterials.2010.02.039 · Cited by 94
Chou, C., Verbaro, D., Tonc, E., Holmgren, M., Cella, M., Colonna, M., Bhattacharya, D., & Egawa, T. (2016) · Immunity · doi:10.1016/j.immuni.2016.07.023 · Cited by 93
“Rosa26creERT2 (Ventura et al., 2007), Ighg1cre (Casola et al., 2006), Aicdacre (Robbiani et al., 2008), Igh / (mMT) (Kitamura et al., 1991), and Il21r / mice (Fröhlich et al., 2007) were from JAX.”
Ubiquitination and deubiquitination: Implications on cancer therapy
Dagar, G., Kumar, R., Yadav, K. K., Singh, M. K., & Pandita, T. K. (2023) · Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms · doi:10.1016/j.bbagrm.2023.194979 · Cited by 96
Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas
THIERS, B. H. (2008) · Yearbook of Dermatology and Dermatologic Surgery · doi:10.1016/s0093-3619(08)70921-3 · Cited by 94
Mouse Models of p53 FunctionsPreprint
Lozano, G. (2009) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a001115 · Cited by 97
“Restoration of p53 functions in sarcomas from p53-null mice and in hepatocellular carcinomas induced by HrasV12 results in tumor regression via a senescence phenotype (Ventura et al. 2007; Xue et al. 2007).”
BackgroundRoh, J., Kang, S. K., Minn, I., Califano, J. A., Sidransky, D., & Koch, W. M. (2010) · Oral Oncology · doi:10.1016/j.oraloncology.2010.10.011 · Cited by 92
Sullivan, K. D., Gallant‐Behm, C. L., Henry, R. E., Fraikin, J.-L., & Espinosa, J. M. (2012) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2012.01.004 · Cited by 96
“The validity of p53 as a therapeutic target has been elegantly proven in animal models where specific activation of p53 in tumors leads to their demise via apoptosis or senescence [187,188].”
Guo, Y., Li, Q., Zhao, G., Zhang, J., Yuan, H., Feng, T., Ou, D., Gu, R. C., Li, S., Li, K., et al. (2021) · Cell Death and Disease · doi:10.1038/s41419-021-04208-3 · Cited by 95
GSDMD drives canonical inflammasome‐induced neutrophil pyroptosis and is dispensable for NETosis
Chauhan, D., Demon, D., Walle, L. V., Paerewijck, O., Zecchin, A., Bosseler, L., Santoni, K., Planès, R., Ribó, S., Fossoul, A., et al. (2022) · EMBO Reports · doi:10.15252/embr.202154277 · Cited by 94
“To determine whether this is also true for neutrophils of the disease-associated Nlrp3 A350V mutant mice, we bred mice that are homozygous for the Nlrp3 A350V allele to transgenic mice that hemizygously expressed the tamoxifen-inducible Cre-ERT2 fusion gene (CreT) (Ventura et al , 2007).”
BRD8 maintains glioblastoma by epigenetic reprogramming of the p53 network
Sun, X. S., Klingbeil, O., Lu, B., Wu, C., Ballon, C., Ouyang, M., Wu, X., Jin, Y., Hwangbo, Y., Huang, Y., et al. (2022) · Nature · doi:10.1038/s41586-022-05551-x · Cited by 96
The Consequence of Oncomorphic TP53 Mutations in Ovarian Cancer
Brachova, P., Thiel, K. W., & Leslie, K. K. (2013) · International Journal of Molecular Sciences · doi:10.3390/ijms140919257 · Cited by 92
“The concept of restoring WT p53 activity is strongly supported by in vitro and in vivo studies as well as several clinical trials showing that restoration of WT p53 function causes rapid tumor regression in mice and prolonged survival in humans [101–105].”
BackgroundLeroy, B., Ballinger, M. L., Baran‐Marszak, F., Bond, G. L., Braithwaite, A. W., Concin, N., Donehower, L. A., El‐Deiry, W. S., Fenaux, P., Gaïdano, G., et al. (2017) · Cancer Research · doi:10.1158/0008-5472.can-16-2179 · Cited by 95
TP53 mutations in cancer: Molecular features and therapeutic opportunities (Review)
Tornesello, M. L. (2024) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2024.5448 · Cited by 105
Identification of potential synthetic lethal genes to p53 using a computational biology approach
Wang, X., & Simon, R. (2013) · BMC Medical Genomics · doi:10.1186/1755-8794-6-30 · Cited by 91
“However, this is a more challenging field in that it is more difficult to develop a drug that reactivates the function of an inactivated gene than to develop a drug that inhibits the function of a hyperactivated gene, although reconstitution of the p53 pathway is believed to be an exciting novel therapeutic challenge…”
BackgroundCancer secretome and inflammation: The bright and the dark sides of NF-κB
Capece, D., Verzella, D., Tessitore, A., Alesse, E., Capalbo, C., & Zazzeroni, F. (2017) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2017.08.004 · Cited by 94
Endogenous Control Mechanisms of FAK and PYK2 and Their Relevance to Cancer Development
Naser, R., Aldehaiman, A., Díaz‐Galicia, E., & Arold, S. T. (2018) · Cancers · doi:10.3390/cancers10060196 · Cited by 90
“However, therapeutic restoration of a functional p53 pool at endogenous levels can have tumor-suppressive effects [146].”
BackgroundPRC2 preserves intestinal progenitors and restricts secretory lineage commitment
Chiacchiera, F., Rossi, A., Jammula, S., Zanotti, M., & Pasini, D. (2016) · The EMBO Journal · doi:10.15252/embj.201694550 · Cited by 94
“…purchased from Jackson Laboratories] were mated with AhCre [kindly provided by Douglas Winton (Ireland et al , 2004)], LGR5eGFP-IRESCre ERT2 (Barker et al , 2007), Rosa26-lsl-LacZ (Soriano, 1999) or Rosa26-CreER T2 (Ventura et al , 2007; purchased from Jackson Laboratories) transgenic strains.”
Role of p53 in the progression of gastric cancer
Busuttil, R. A., Zapparoli, G. V., Haupt, S., Fennell, C. M., Wong, S. Q., Pang, J., Takeno, E. A., Mitchell, C., Costanzo, N. D., Fox, S. B., et al. (2014) · Oncotarget · doi:10.18632/oncotarget.2434 · Cited by 89
“com/oncotarget successfully demonstrated in mouse models whereby temporal restoration of p53 resulted in tumour regression [31-33].”
Background
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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