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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“resulting in two apparently opposing roles: on one hand, tumor inhibition via maintenance of prolonged to indefinite growth arrest and immune clearance of the senescent cells (Bartkova et al., 2005; Chen et al., 2005; Guerra et al., 2011; Kang et al., 2011; Reimann et al., 2010; Ventura et al., 2007; Xue et al., 2007)…”
BackgroundSchulz‐Heddergott, R., Stark, N., Edmunds, S. J., Li, J., Conradi, L., Bohnenberger, H., Ceteci, F., Greten, F. R., Dobbelstein, M., & Moll, U. M. (2018) · Cancer Cell · doi:10.1016/j.ccell.2018.07.004 · Cited by 243
“To remove the mutp53 allele with Tamoxifen, we crossed mice containing the p53floxQ allele with Rosa26CreERT2 (‘ERT2’) transgenic mice (Ventura et al., 2007).”
MethodCells of origin in osteosarcoma: Mesenchymal stem cells or osteoblast committed cells?
Mutsaers, A. J., & Walkley, C. R. (2014) · Bone · doi:10.1016/j.bone.2014.02.003 · Cited by 233
“These models, together with a number of modified germ-line p53 alleles [51–53] have demonstrated the unique role for p53 mutation in the initiation and maintenance of OS.”
BackgroundStat5 is indispensable for the maintenance of bcr/abl‐positive leukaemia
Hoelbl‐Kovacic, A., Schuster, C., Kovačic, B., Zhu, B., Wickre, M. C., Hoelzl, M. A., Fajmann, S., Grebien, F., Warsch, W., Stengl, G., et al. (2010) · EMBO Molecular Medicine · doi:10.1002/emmm.201000062 · Cited by 238
“…Vienna, Austria. þ43-1-4277-9641; DKFZ), Heidelberg n Academy of tumour maintenance is associated with rewiring of signalling pathways and by acquiring additional genetic mutations (e.g. mutations or deletions of Trp53 or Bcl-2 over-expression) (Letai et al, 2004; Sherr, 2004; Ventura et al, 2007).”
Quercetin: a natural compound for ovarian cancer treatment
Shafabakhsh, R., & Asemi, Z. (2019) · Journal of Ovarian Research · doi:10.1186/s13048-019-0530-4 · Cited by 231
In Vivo Imaging in CancerPreprint
Condeelis, J. S., & Weissleder, R. (2010) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a003848 · Cited by 231
“…in genetically engineered mouse models with temporal and tissue-specific control of activation of oncogenes and/or tumor-suppressors, because they permit the study of oncogenic transformation and to assess drug action, resistance, and toxicity (Sharpless and Depinho 2006; Ventura et al. 2007).”
BackgroundSelf-citationp53 as a target for the treatment of cancer
Duffy, M. J., Synnott, N. C., McGowan, P. M., Crown, J. P., O’Connor, D. P., & Gallagher, W. M. (2014) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2014.10.004 · Cited by 239
“Despite this, proof of principle that restoration and stabilization of WT p53 can result in tumor regression has been demonstrated in a number of different animal models [22–24].”
BackgroundResultActions of human telomerase beyond telomeres
Cong, Y., & Shay, J. W. (2008) · Cell Research · doi:10.1038/cr.2008.74 · Cited by 231
Liu, M., Li, C., Pazgier, M., Li, C., Mao, Y., Lv, Y., Gu, B., Wei, G., Yuan, W., Zhan, C., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1008930107 · Cited by 236
Senescence: a new weapon for cancer therapy
Acosta, J. C., & Gil, J. (2012) · Trends in Cell Biology · doi:10.1016/j.tcb.2011.11.006 · Cited by 235
Computational identification of a transiently open L1/S3 pocket for reactivation of mutant p53
Wassman, C. D., Baronio, R., Demir, Ö., Wallentine, B. D., Chen, C.-K., Hall, L., Salehi, F., Lin, D., Chung, B. P., Hatfield, G. W., et al. (2013) · Nature Communications · doi:10.1038/ncomms2361 · Cited by 226
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“Recently, it has been shown that reactivation of p53 in mouse cancer models induced rapid tumor regression by the induction of apoptosis or cellular senescence depending on the tumor type (5).”
The cell fate: senescence or quiescence
Terzi, M. Y., Izmirli, M., & Gogebakan, B. (2016) · Molecular Biology Reports · doi:10.1007/s11033-016-4065-0 · Cited by 208
“p53 (TP53; tumor protein p53) ?G1,G1/S or G2 cell cycle arrests, apoptosis [23, 24, 35] ?G0 arrest, growth inhibition [9]”
BackgroundDecline in IGF1 in the bone marrow microenvironment initiates hematopoietic stem cell aging
Young, K., Eudy, E., Bell, R., Loberg, M. A., Stearns, T., Sharma, D., Velten, L., Haas, S., Filippi, M.-D., & Trowbridge, J. J. (2021) · Cell Stem Cell · doi:10.1016/j.stem.2021.03.017 · Cited by 216
Kennedy, A. L., Morton, J. P., Manoharan, I., Nelson, D. M., Jamieson, N. B., Pawlikowski, J. S., McBryan, T., Doyle, B., McKay, C., Oien, K. A., et al. (2011) · Molecular Cell · doi:10.1016/j.molcel.2011.02.020 · Cited by 213
“Underscoring the ability of senescence to block tumor growth, its reactivation in murine tumors is associated with tumor regression (Ventura et al., 2007; Xue et al., 2007).”
VEGF‐C is required for intestinal lymphatic vessel maintenance and lipid absorption
Nurmi, H. J., Saharinen, P., Zarkada, G., Zheng, W., Robciuc, M. R., & Alitalo, K. K. (2015) · EMBO Molecular Medicine · doi:10.15252/emmm.201505731 · Cited by 210
Synthetic Lethality in Cancer Therapeutics: The Next Generation
Setton, J. S., Zinda, M. J., Riaz, N., Durocher, D., Zimmermann, M., Koehler, M. T., Reis-Filho, J. S., & Powell, S. N. (2021) · Cancer Discovery · doi:10.1158/2159-8290.cd-20-1503 · Cited by 214
Tumour suppression by p53: the importance of apoptosis and cellular senescence
Zuckerman, V., Wolyniec, K., Sionov, R. V., Haupt, S., & Haupt, Y. (2009) · The Journal of Pathology · doi:10.1002/path.2584 · Cited by 222
“Interestingly, restoration of p53 in two types of solid tumour, radiation-induced sarcomas and hepatocellular carcinoma, led to cellular senescence and tumour clearance [105,106].”
BackgroundMolecular biology of lung cancer: Clinical implications
Fong, K. M., & Minna, J. D. (2002) · Clinics in Chest Medicine · doi:10.1016/s0272-5231(03)00062-5 · Cited by 211
Cellular responses to reactive oxygen species-induced DNA damage and aging
Bertram, C., & Hass, R. (2008) · Biological Chemistry · doi:10.1515/bc.2008.031 · Cited by 217
Nucleophosmin and its complex network: a possible therapeutic target in hematological diseases
Colombo, E., Alcalay, M., & Pelicci, P. G. (2011) · Oncogene · doi:10.1038/onc.2010.646 · Cited by 223
Zhuang, D., Mannava, S., Grachtchouk, V., Tang, W. H., Patil, S. B., Wawrzyniak, J. A., Berman, A. E., Giordano, T. J., Prochownik, E. V., Soengas, M. S., et al. (2008) · Oncogene · doi:10.1038/onc.2008.258 · Cited by 219
“…C-MYC depletion in melanoma cells or by BRAFV600E and NRASQ61R overexpression in melanocytes occur independent of p53 or p16INK4A Oncogene-induced senescence phenotypes in mouse cells have been previously shown to depend on p53 and/or p16 (Ventura et al., 2007; Wu et al., 2007; Xue et al., 2007).”
BackgroundIsoform-specific p73 knockout mice reveal a novel role for ΔNp73 in the DNA damage response pathwayPreprint
Wilhelm, M., Rufini, A., Wetzel, M. K., Tsuchihara, K., Inoue, S., Tomasini, R., Itie-YouTen, A., Wakeham, A. C., Arsenian‐Henriksson, M., Melino, G., et al. (2010) · Genes & Development · doi:10.1101/gad.1873910 · Cited by 214
“vivo (Ventura et al. 2007; Xue et al. 2007), we did detect an increase in DNp73-deficient tumors of the senescence markers senescence-associated b-galactosidase (SAb-gal), p16, and DcR2 (Fig.”
BackgroundOlsson, A., Manzl, C., Strasser, A., & Villunger, A. (2007) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4402196 · Cited by 204
“oncogene-induced senescence is also critical for the tumour suppressive function of p53, as indicated by studies with mice expressing conditionally active forms of p53.(142,143) It is presently not known whether activation of the senescence pathway is defective in cells expressing p53 or p53 mutant protein.”
BackgroundDayal, S., Sparks, A., Jacob, J., Allende-Vega, N., Lane, D. P., & Saville, M. K. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m805871200 · Cited by 203
Swarbrick, A., Woods, S. L., Shaw, A., Balakrishnan, A., Phua, Y. W., Nguyen, A., Chanthery, Y. H., Lim, L., Ashton, L. J., Judson, R. L., et al. (2010) · Nature Medicine · doi:10.1038/nm.2227 · Cited by 202
Molecular Pathways: Regulation and Therapeutic Implications of Multidrug Resistance
Chen, K. G., & Sikic, B. I. (2012) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-11-1590 · Cited by 197
Deconstructing p53 transcriptional networks in tumor suppression
Bieging, K. T., & Attardi, L. D. (2012) · Trends in Cell Biology · doi:10.1016/j.tcb.2011.10.006 · Cited by 194
Translating p53-based therapies for cancer into the clinic
Peuget, S., Zhou, X., & Selivanova, G. (2024) · Nature reviews. Cancer · doi:10.1038/s41568-023-00658-3 · Cited by 208
Two tissue-resident progenitor lineages drive distinct phenotypes of heterotopic ossification
Dey, D., Bagarova, J., Hatsell, S. J., Armstrong, K. A., Huang, L., Ermann, J., Vonner, A. J., Shen, Y., Mohedas, A. H., Lee, A. M., et al. (2016) · Science Translational Medicine · doi:10.1126/scitranslmed.aaf1090 · Cited by 195
Targeting the p53 signaling pathway in cancer therapy – the promises, challenges and perils
Stegh, A. H. (2012) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728222.2011.643299 · Cited by 198
“Confirming important roles of p53 in cancer suppression, these studies showed that re-activation of p53 in established tumors can temporarily stop tumor growth; the precise cellular mechanism is cancer-specific, as lymphomas die by apoptosis, whereas p53 restoration in sarcomas and liver carcinomas leads to growth arr…”
Background20 years studying p53 functions in genetically engineered mice
Donehower, L. A., & Lozano, G. (2009) · Nature reviews. Cancer · doi:10.1038/nrc2731 · Cited by 196
“The use of such conditionally activated wild-type p53 models was also used by the Evan, Jacks and Lowe laboratories to show that the restoration of p53 function can cause dramatic tumour regressio”
MethodTumor Evolution as a Therapeutic Target
Amirouchene-Angelozzi, N., Swanton, C., & Bardelli, A. (2017) · Cancer Discovery · doi:10.1158/2159-8290.cd-17-0343 · Cited by 197
“However, with the exception of p53 loss in preclinical models (80), dependency of tumor cells on specific mutagenic alterations has yet to be proven, and the efficacy of APOBEC inhibition awaits further validation.”
BackgroundCellular senescence in cancer: from mechanisms to detection
Ou, H., Hoffmann, R. J., González‐López, C., Doherty, G. J., Korkola, J. E., & Muñoz‐Espín, D. (2020) · Molecular Oncology · doi:10.1002/1878-0261.12807 · Cited by 208
Size Does Matter: Why Polyploid Tumor Cells are Critical Drug Targets in the War on Cancer
Coward, J. I. G., & Harding, A. S. (2014) · Frontiers in Oncology · doi:10.3389/fonc.2014.00123 · Cited by 197
Zimmermann, M., Kibe, T., Kabir, S., & de Lange, T. (2014) · Genes & Development · doi:10.1101/gad.251611.114 · Cited by 189
“The TRF1, BLM, TPP1, Rap1, 53BP1 / , and ROSA Cre-ER mice were published previously (Ward et al. 2003; Chester et al. 2006; Ventura et al. 2007; Sfeir et al. 2009, 2010; Kibe et al. 2010).”
MethodGuo, J., Cheng, J., Zheng, N., Zhang, X., Dai, X., Zhang, L., Hu, C.-J., Wu, X., Jiang, Q., Wu, D., et al. (2021) · Advanced Science · doi:10.1002/advs.202004303 · Cited by 198
Transient Inactivation of Rb and ARF Yields Regenerative Cells from Postmitotic Mammalian Muscle
Pajcini, K. V., Corbel, S. Y., Sage, J., Pomerantz, J. H., & Blau, H. M. (2010) · Cell stem cell · doi:10.1016/j.stem.2010.05.022 · Cited by 193
Assessing cell and organ senescence biomarkers
de Jesus, B. B., & Blasco, M. A. (2012) · Circulation Research · doi:10.1161/circresaha.111.247866 · Cited by 187
Recent Advances in p53 Research and Cancer Treatment
Suzuki, K., & Matsubara, H. (2011) · BioMed Research International · doi:10.1155/2011/978312 · Cited by 191
“An animal model showed the reactivation of wildtype p53 to result in efficient tumor regression, including regression of lymphoma [40, 41] and liver carcinoma [38].”
BackgroundThe Skp2 Pathway: A Critical Target for Cancer Therapy
Cai, Z., Moten, A., Peng, D., Hsu, C.-C., Pan, B., Manne, R., Li, H., & Lin, H. (2020) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2020.01.013 · Cited by 186
Brooks, C. L., & Gu, W. (2011) · FEBS Letters · doi:10.1016/j.febslet.2011.05.022 · Cited by 186
“Animal studies have shown that the reactivation of p53 in p53 null tumors induces tumor regression [80–82].”
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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