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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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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 function leads to tumour regression in vivo
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Antitumor mechanisms when pRb and p53 are genetically inactivated
Zhu, L., Lu, Z., & Zhao, H.-T. (2014) · Oncogene · doi:10.1038/onc.2014.399 · Cited by 49
“In contrast, tumors induced by irradiation of newborns (29), viral expression of HRASG12V (30), or Eμ-Myc (31) in the absence of p53 strongly activated restored p53 leading to complete tumor regression.”
BackgroundWu, W., Xu, C., Ling, X., Fan, C., Buckley, B., Chernov, M. V., Ellis, L., Li, F., Muñoz, I. G., & Wang, X. (2015) · Cell Death and Disease · doi:10.1038/cddis.2015.358 · Cited by 46
“The p53-based therapy relies on druginduced apoptosis.(4) In sharp contrast to Nutlin3a, MMRi64 preferentially induces apoptosis in leukemia/lymphoma cells, probably due to PUMA induction and simultaneous shutdown of pro-growth-arrest p21 (Figures 4 and 5a), and downregulation of Mdm2 andMdmX.”
BackgroundYokoyama, T., Nakatake, M., Kuwata, T., Couzinet, A., Goitsuka, R., Tsutsumi, S., Aburatani, H., Valk, P. J. M., Delwel, R., & Nakamura, T. (2016) · Journal of Clinical Investigation · doi:10.1172/jci81516 · Cited by 46
“Bone marrow cells were prepared from 8-week-old female Rosa26-Cre-ERT2 mice (58) 5 days after injection of 150 mg 5-fluorouracil/kg body weight (Kyowa Hakko Kogyo).”
MethodWang, B., Wu, H., Chai, C., Lewis, J. D., Pichiorri, F., Eisenstat, D. D., Pomeroy, S. L., & Leng, R. P. (2017) · Cancer Letters · doi:10.1016/j.canlet.2017.04.038 · Cited by 46
Targeted therapy for Kaposi's sarcoma and Kaposi's sarcoma-associated herpesvirus
Dittmer, D. P., & Krown, S. E. (2007) · Current Opinion in Oncology · doi:10.1097/cco.0b013e3281eb8ea7 · Cited by 46
Oncogene-induced senescence: An essential role for Runx
Terry, A., Cameron, E. R., Neil, J. C., & Kilbey, A. (2008) · Cell Cycle · doi:10.4161/cc.6368 · Cited by 51
Pawlikowski, J. S., Adams, P. D., & Nelson, D. M. (2013) · Journal of Cell Science · doi:10.1242/jcs.109728 · Cited by 52
“In addition, other strategies for pro-senescence therapy have been proposed, including inhibition of telomerase activity and alteration of CDK or CDK regulators (Campaner et al., 2010; Chen et al., 2005; Harley, 2008; Kennedy et al., 2011; Nardella et al., 2011; Puyol et al., 2010; Ventura et al., 2007; Wall et al., 2…”
BackgroundMethodInfluentialGuo, G., & Cui, Y. R. (2015) · Journal for ImmunoTherapy of Cancer · doi:10.1186/s40425-015-0053-5 · Cited by 47
“In fact, recent results from our laboratory and others have demonstrated that p53 dysfunction skews tumor milieu towards pro-tumor inflammation [25-27], whereas p53 reactivation or restoration reverses the immunological landscape towards antitumor immunity [28-30].”
BackgroundRew, Y., Sun, D., Yan, X., Beck, H. P., Canon, J. R., Chen, A., Duquette, J., Eksterowicz, J. E., Fox, B. M., Fu, J., et al. (2014) · Journal of Medicinal Chemistry · doi:10.1021/jm501550p · Cited by 45
An Expeditious Synthesis of the MDM2–p53 Inhibitor AM-8553
Lucas, B. S., Fisher, B., McGee, L. R., Olson, S. H., Medina, J. C., & Cheung, E. Y. (2012) · Journal of the American Chemical Society · doi:10.1021/ja305123v · Cited by 47
Rigatti, M. J., Verma, R., Belinsky, G. S., Rosenberg, D. W., & Giardina, C. A. (2011) · Molecular Carcinogenesis · doi:10.1002/mc.20795 · Cited by 45
Kamat, C. D., Shmueli, R. B., Connis, N., Rudin, C. M., Green, J. J., & Hann, C. L. (2013) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-12-0956 · Cited by 45
“ration of p53 in these models results in potent antitumor activity in a cell-type–specific manner; TP53 reexpression induces apoptosis in autochthonous lymphomas but senescence in sarcoma and hepatocellular carcinoma models (10, 11).”
Wu, L., Wang, Z., Zong, S., Chen, H., Wang, C., Xu, S., & Cui, Y. (2013) · The Analyst · doi:10.1039/c3an00181d · Cited by 45
TRIM8 anti-proliferative action against chemo-resistant renal cell carcinoma
Caratozzolo, M. F., Valletti, A., Gigante, M., Aiello, I., Mastropasqua, F., Marzano, F., Ditonno, P., Carrieri, G., Simonnet, H., D’Erchia, A. M., et al. (2014) · Oncotarget · doi:10.18632/oncotarget.2081 · Cited by 45
“The latter approach greatly expands the options in target selection for therapeutic intervention and the first studies performed with mouse models able to restore p53 activity by means of a genetic switch have shown that this strategy can lead to regression of tumours and increased survival of the animal [49-51].”
BackgroundEffect of Cellular Senescence on the Growth of HER2-Positive Breast Cancers
Fluck, M. F. Z., Morancho, B., Vicario, R., Luque-García, A., Escorihuela, M., Villanueva, J., Rubio, I. T., & Arribas, J. (2015) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djv020 · Cited by 45
Combining Oncolytic Virotherapy with p53 Tumor Suppressor Gene Therapy
Bressy, C., Hastie, E. L., & Grdzelishvili, V. Z. (2017) · Molecular Therapy — Oncolytics · doi:10.1016/j.omto.2017.03.002 · Cited by 50
Neutral lineage tracing of proliferative embryonic and adult mammary stem/progenitor cells
Lloyd‐Lewis, B., Davis, F. M., Harris, O. B., Hitchcock, J. R., & Watson, C. J. (2018) · Development · doi:10.1242/dev.164079 · Cited by 45
Using Cre-recombinase-driven Polylox barcoding for in vivo fate mapping in mice
Pei, W., Wang, X., Rößler, J., Feyerabend, T. B., Höfer, T., & Rodewald, H.-R. (2019) · Nature Protocols · doi:10.1038/s41596-019-0163-5 · Cited by 48
CARF Is a Vital Dual Regulator of Cellular Senescence and Apoptosis
Hasan, M. K., Cheung, C., Kaul, Z., Shah, N., Sakaushi, S., Sugimoto, K., Oka, S., Kaul, S. C., & Wadhwa, R. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m805778200 · Cited by 45
Zhang, Y., Dong, Y., Melkus, M. W., Yin, S., Tang, S.-N., Jiang, P., Pramanik, K., Wu, W., Kim, S., Ye, M., et al. (2018) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-17-1296 · Cited by 55
“In vivo restoration of P53 function in P53dysfuntional sarcomas or liver tumors led to significant tumor regression (40, 41) and surprisingly, through P53-mediated senescence and innate immune cells, instead of apoptosis (40).”
BackgroundRole of senescence induction in cancer treatment
Qin, S., Schulte, B. A., & Wang, G. Y. (2018) · World Journal of Clinical Oncology · doi:10.5306/wjco.v9.i8.180 · Cited by 44
Lowe, K. L., Navarro‐Núñez, L., Bénézech, C., Nayar, S., Kingston, B. L., Nieswandt, B., Barone, F., Watson, S. P., Buckley, C. D., & Desanti, G. E. (2015) · European Journal of Immunology · doi:10.1002/eji.201445314 · Cited by 49
Drakos, E., Atsaves, V., Schlette, E. J., Li, J.-D., Papanastasi, E., Rassidakis, G. Z., & Medeiros, L. J. (2009) · Leukemia · doi:10.1038/leu.2009.180 · Cited by 44
Tur, M. K., Neef, I., Jost, E., Galm, O., Jäger, G., Stöcker, M., Ribbert, M., Osieka, R., Klinge, U., & Barth, S. (2009) · Journal of Immunotherapy · doi:10.1097/cji.0b013e31819f1cb6 · Cited by 44
“By using a more targeted approach to cancer therapy, it has previously been shown that tumor development can be suppressed by reestablishing the expression of individual tumor suppressors such as the retinoblastoma protein (Rb)(47) and tumor protein 53 (p53).(48,49) In each case, however, the expression construct was…”
BackgroundJung, H. S., Erkin, Ö. C., Kwon, M. J., Kim, S. H., Jung, J. I., Oh, Y., Her, S., Ju, W., Choi, Y., Song, S. Y., et al. (2011) · International Journal of Cancer · doi:10.1002/ijc.26197 · Cited by 46
“Three new reports have shown that the restoration of TP53 function in established mouse tumor models leads to the regression of tumors through apoptosis, senescence or the activation of innate immunity.(23,34,35) We also noticed that the maintenance of xenograft tumors required the persistent inactivation of TP53 and…”
BackgroundMethodGrabow, S., Delbridge, A. R. D., Valente, L. J., & Strasser, A. (2014) · Blood · doi:10.1182/blood-2014-09-601567 · Cited by 44
“In accordance with this hypothesis, it was shown that, although restoration of p53 caused apoptosis in p53 thymic lymphomas, this caused cellular senescence in p53 sarcomas.(43) For the development of novel therapeutic strategies, it is essential to know which pro-survival BCL-2 family member is critical for the susta…”
Lee, T., Paola, D. D., Malina, A., Mills, J. R., Kreps, A., Große, F., Tang, H., Zannis‐Hadjopoulos, M., Larsson, O. S., & Pelletier, J. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.568535 · Cited by 43
“This indicates that induction of senescence is highly dependent on the particular biological wiring of the cell type in question, a notion supported by previous studies (64).”
ResultSawosz, E., Jaworski, S., Kutwin, M., Vadalasetty, K. P., Grodzik, M., Wierzbicki, M., Kurantowicz, N., Strojny, B., Hotowy, A., Lipińska, L., et al. (2015) · International Journal of Molecular Sciences · doi:10.3390/ijms161025214 · Cited by 44
“of the MDM2 binding domain without deregulation and deactivation of p53 protein could benefit anticancer therapy [56,57].”
BackgroundTheranostics in the Growing Field of Personalized Medicine: An Analytical Chemistry Perspective
Crawley, N., Thompson, M. E., & Romaschin, A. D. (2013) · Analytical Chemistry · doi:10.1021/ac4038812 · Cited by 44
Trans-chalcone increases p53 activity via DNAJB1/HSP40 induction and CRM1 inhibition
SILVA, G. H. D. O., Marins, M., Chaichanasak, N., Yoon, Y., Fachin, A. L., Pinhanelli, V. C., Regasini, L. O., dos Santos, M. B., Ayusso, G. M., Marques, B. D. C., et al. (2018) · PLoS ONE · doi:10.1371/journal.pone.0202263 · Cited by 44
Anticancer effect of ursolic acid via mitochondria‑dependent pathways (Review)
Feng, X., & Su, X. (2019) · Oncology Letters · doi:10.3892/ol.2019.10171 · Cited by 47
Markov state models and NMR uncover an overlooked allosteric loop in p53
de Barros, E. P., Demir, Ö., Soto, J., Cocco, M. J., & Amaro, R. E. (2020) · Chemical Science · doi:10.1039/d0sc05053a · Cited by 45
Regulation of RB Transcription In Vivo by RB Family Members
Burkhart, D. L., Ngai, L. K., Roake, C. M., Viatour, P., Thangavel, C., Ho, V. M., Knudsen, E. S., & Sage, J. (2010) · Molecular and Cellular Biology · doi:10.1128/mcb.00952-09 · Cited by 45
“We crossed these p130 mice to the Rosa26 allele to be able to delete p130 acutely in a broad number of cell types (51).”
MethodEndogenous retinoic acid signaling is required for maintenance and regeneration of cornea
Kumar, S., Dollé, P., Ghyselinck, N. B., & Duester, G. (2016) · Experimental Eye Research · doi:10.1016/j.exer.2016.11.009 · Cited by 44
“We generated Aldh1a1,2,3-flox/flox;Rosa26-Cre/ERT2 mice by crossing Aldh1a1,2,3-flox/flox mice with mice carrying the Rosa26-Cre/ERT2 transgene that allows widespread induction of Cre following tamoxifen treatment (Ventura et al., 2007).”
MethodSmall molecules that bind the Mdm2 RING stabilize and activate p53
Roxburgh, P., Hock, A. K., Dickens, M. P., Mezna, M., Fischer, P. M., & Vousden, K. H. (2012) · Carcinogenesis · doi:10.1093/carcin/bgs092 · Cited by 43
Hu, Y., Yang, C., Amorim, T., Maqbool, M., LIN, J. L.-C., Li, C., Fang, C., Li, X., Kwart, A. H., Hua, F., et al. (2020) · Cancer Research · doi:10.1158/0008-5472.can-20-1010 · Cited by 43
Breathing new insights into the role of mutant p53 in lung cancer
Chen, T., Ashwood, L. M., Kondrashova, O., Strasser, A., Kelly, G. L., & Sutherland, K. D. (2024) · Oncogene · doi:10.1038/s41388-024-03219-6 · Cited by 49
Complex oncogene dependence in microRNA-125a–induced myeloproliferative neoplasms
Guo, S., Bai, H., Megyola, C. M., Halene, S., Krause, D. S., Scadden, D. T., & Lü, J. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1213196109 · Cited by 42
Yu, S., Yehia, G., Wang, J., Stypulkowski, E., Sakamori, R., Jiang, P., Hernández-Enríquez, B., Tran, T. S., Bonder, E. M., Guo, W., et al. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.538223 · Cited by 43
“To determine whether Rab11a embryos died during the implantation stages, we employed an inducible Rab11a deletion strategy using Rosa26-CreER mice, which globally ablate gene targets in a tamoxifen-inducible fashion (38).”
MethodMicroRNAs: New Players in Multiple Myeloma
Pichiorri, F., Luca, L. D., & Aqeilan, R. I. (2011) · Frontiers in Genetics · doi:10.3389/fgene.2011.00022 · Cited by 43
“Although regulation of the p53 pathway is not fully understood at the molecular level, it has been well established that activated p53 suppresses cancer progression, underscoring why cancer cells have developed multiple mechanisms to disable p53 function (Danovi et al., 2004; Ventura et al., 2007).”
BackgroundMerkel, C. A., Soares, R. B. D. S., de Carvalho, A. C. V., Zanatta, D. B., Bajgelman, M. C., Fratini, P., Costanzi-Strauss, E., & Strauss, B. E. (2010) · BMC Cancer · doi:10.1186/1471-2407-10-316 · Cited by 43
“Background For those tumors that retain wild type p53 (p53 wt), maintenance of the tumor phenotype depends on its ability to hold p53 wt in an inactive form even long after the initial transformation events [1-4].”
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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