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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The Bulk of Autotaxin Activity Is Dispensable for Adult Mouse Life
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BackgroundInfluentialPredicting Positive p53 Cancer Rescue Regions Using Most Informative Positive (MIP) Active Learning
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“Reactivated p53 holds great therapeutic promise because animal models have shown that reintroduction of active p53, even in advanced tumors, leads to tumor regression [16–18].”
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BackgroundATM and MET kinases are synthetic lethal with nongenotoxic activation of p53
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“…Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. in different tumor types (Feldser et al., 2010; Hill et al., 2015; Junttila et al., 2010; Martins et al., 2006; Ventura et al., 2007; Xue et al., 2007).”
BackgroundDeficiency of Notch signaling in pericytes results in arteriovenous malformations
Nadeem, T., Bogue, W., Bigit, B., & Cuervo, H. (2020) · JCI Insight · doi:10.1172/jci.insight.125940 · Cited by 70
“To verify efficient loss of Notch3 using the newly generated Notch3flox line, we crossed it with the ROSA26-CreERT2 (39) mouse line to generate ROSA26-CreERT2;Notch3fl/fl mice and evaluated the levels of Notch3 in the retinas of P14 mice treated with tamoxifen at P1–P3.”
MethodDisrupting Roquin-1 interaction with Regnase-1 induces autoimmunity and enhances antitumor responses
Behrens, G., Edelmann, S. L., Raj, T., Kronbeck, N., Monecke, T., Davydova, E., Wong, E. H., Kifinger, L., Giesert, F., Kirmaier, M. E., et al. (2021) · Nature Immunology · doi:10.1038/s41590-021-01064-3 · Cited by 66
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Dangerous habits of a security guard: the two faces of p53 as a drug target
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“The validity of such an approach is supported by numerous demonstrations of the anti-tumor effect of p53 activated either by genetic manipulation (35,36) or by small molecules that target its interaction with inhibitory proteins or restore the functionality of mutant p53 (37).”
BackgroundInitiation of MLL-rearranged AML is dependent on C/EBPα
Ohlsson, E., Hasemann, M. S., Willer, A., Lauridsen, F. K. B., Rapin, N., Jendholm, J., & Porse, B. T. (2013) · The Journal of Experimental Medicine · doi:10.1084/jem.20130932 · Cited by 67
“This suggests that residual activity of C/EBP is required for leukemogenesis, and the current notion is that C/EBP activity is required for AMLs to attain their myeloid identity (Wagner et al., 2006).”
Thiosemicarbazones Functioning as Zinc Metallochaperones to Reactivate Mutant p53
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“Restoring wild type (WT) p53 function by genetic means in mouse models of cancer triggers potent anti-cancer activity (Ventura et al., 2007; Xue et al., 2007).”
BackgroundLi, H., Zhang, Y., Ströse, A., Tedesco, D., Gurova, K. V., & Selivanova, G. (2014) · Cell Death and Differentiation · doi:10.1038/cdd.2014.69 · Cited by 65
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“(9) showed that restoring endogenous p53 expression in mice Received 12/26/07; revised 3/10/08; accepted 3/16/08.”
BackgroundUpdates on p53: modulation of p53 degradation as a therapeutic approach
Dey, A., Verma, C. S., & Lane, D. P. (2008) · British Journal of Cancer · doi:10.1038/sj.bjc.6604098 · Cited by 65
“More recently, small molecule inhibitors of transcription (the cyclin-dependent kinase (CDK) inhibitors) have been found to block Mdm2 expression and activate p53 as discussed later.”
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VEGF-C protects the integrity of the bone marrow perivascular niche in mice
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The Dual Role Played by p21 May Influence the Apoptotic or Anti-Apoptotic Fate in Cancer
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“p53 reactivation resulted in apoptotic increase and related to caspase-3 and p21 induction [93].”
BackgroundWild type p53 reactivation: From lab bench to clinic
Selivanova, G. (2014) · FEBS Letters · doi:10.1016/j.febslet.2014.03.049 · Cited by 68
Hemostasis stimulates lymphangiogenesis through release and activation of VEGFC
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New copper complexes inducing bimodal death through apoptosis and autophagy in A549 cancer cells
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The effects of metabolism on the immune microenvironment in colorectal cancer
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“…ERK1/2 activation, inhibiting p53 and decreasing the likelihood of exerting immune effects in the TME, thereby accelerating tumor progression [36, 83]; and 3) DCA can upregulate β -linked proteins, allowing regulatory T cells to differentiate in a proin fl ammatory direction, which in turn…”
BackgroundTransforming growth factor-β signaling is constantly shaping memory T-cell population
Ma, C., & Zhang, N. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1510119112 · Cited by 64
“To specifically determine the role of TGF-β during late stages of memory T-cell differentiation, we used a mouse line carrying a CreEstrogen Receptor T2 (ER-cre) allele targeted to the ubiquitously expressed ROSA26 locus (23) to temporally control the expression of TGF-β receptor II (TGF-βRII).”
MethodNaderi, E. H., Findley, H. W., Ruud, E., Blomhoff, H. K., & Naderi, S. (2009) · Blood · doi:10.1182/blood-2009-02-204883 · Cited by 64
Small molecule compounds targeting the p53 pathway: are we finally making progress?
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“Restoration of p53 function lead to apoptosis in lymphomas and senescence in sarcomas [12].”
BackgroundLang, M., Wither, R. G., Colic, S., Wu, C., Monnier, P. P., Bardakjian, B. L., Zhang, L., & Eubanks, J. H. (2013) · Human Molecular Genetics · doi:10.1093/hmg/ddt421 · Cited by 63
“This transgenic mouse line has been shown previously to express the estrogen receptor/cre recombinase transgene throughout the brain and body, and target both glial cells and neurons throughout the brain (32).”
BackgroundMethodDifferentiation-induced skin cancer suppression by FOS, p53, and TACE/ADAM17
Guinea‐Viniegra, J., Zenz, R., Scheuch, H., Jiménez, M., Bakiri, L., Petzelbauer, P., & Wagner, E. F. (2012) · Journal of Clinical Investigation · doi:10.1172/jci63103 · Cited by 64
Liu, Q., Chen, L., Atkinson, J. M., Claxton, D. F., & Wang, H. (2016) · Cell Death and Disease · doi:10.1038/cddis.2016.264 · Cited by 64
“All animals were bred at the Penn State College of Medicine and genotyped as previously described.(56,57) Age- and sex-matched animals were used for all animal studies, and all studies were carried out without blinding.”
MethodDiscrete cytosolic macromolecular BRAF complexes exhibit distinct activities and composition
Diedrich, B., Rigbolt, K. T. G., Röring, M., Herr, R., Kaeser-Pebernard, S., Gretzmeier, C., Murphy, R. F., Brummer, T., & Dengjel, J. (2017) · The EMBO Journal · doi:10.15252/embj.201694732 · Cited by 64
“After embryo transfer into our facility, mice were maintained on a C57BL/6 background and then mated with Rosa26::CreERT2 mice (Ventura et al , 2007), also backcrossed to a C57BL/6 background.”
Jung, H., Kim, S.-W., Kim, M., Hong, J., Yu, D., Kim, J. H., Lee, Y., Kim, S., Woo, D., Shin, H., et al. (2019) · Nature Communications · doi:10.1038/s41467-018-08282-8 · Cited by 64
High-performance chemical- and light-inducible recombinases in mammalian cells and mice
Weinberg, B. H., Cho, J. H., Agarwal, Y., Pham, N. T. H., Galva, L. D. C., Walkosz, M., Ortega, C. E., Trexler, M., Tague, N., Law, B., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-12800-7 · Cited by 65
Inhibition of Nuclear Pore Complex Formation Selectively Induces Cancer Cell Death
Sakuma, S., Raı́ces, M., Borlido, J., Guglielmi, V., Zhu, E. Y. S., & D’Angelo, M. A. (2020) · Cancer Discovery · doi:10.1158/2159-8290.cd-20-0581 · Cited by 60
“To determine if primary cells also arrest in response to inhibition of NPC formation we generated a conditional Nup160 knockout mouse line in which exon 4 is flanked by loxP sites (Nup160f/f) and crossed it with a mouse line constitutively expressing a tamoxifenregulated Cre recombinase (R26-CreERT2) (28), which allow…”
Triangular Relationship between p53, Autophagy, and Chemotherapy Resistance
Xu, J., Patel, N. H., & Gewirtz, D. A. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21238991 · Cited by 66
“In the nucleus, p53 induces autophagy by regulating the mTOR pathway in a transcription-dependent manner, as well as transcriptional regulation of key autophagy-related genes (ATGs) [39,60].”
BackgroundStructural and Drug Targeting Insights on Mutant p53
Gomes, A. S., Ramos, H., Inga, A., Sousa, E., & Saraiva, L. (2021) · Cancers · doi:10.3390/cancers13133344 · Cited by 63
Glutathione synthesis in the mouse liver supports lipid abundance through NRF2 repression
Asantewaa, G., Tuttle, E. T., Ward, N. P., Kang, Y. P., Kim, Y., Kavanagh, M. E., Girnius, N., Chen, Y., Rodriguez, K., Hecht, F., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-50454-2 · Cited by 69
“To better understand the importance of GSH in adult mammals, we developed an inducible, whole-body Gclc KO mouse by breeding the Gclc f/f mouse strain 30 with the Rosa26-CreERT2 mouse strain 31 .”
BackgroundMethodAdvances in adenovirus-mediated p53 cancer gene therapy
Tazawa, H., Kagawa, S., & Fujiwara, T. (2013) · Expert Opinion on Biological Therapy · doi:10.1517/14712598.2013.845662 · Cited by 66
“Since mesenchymal types of malignant tumors, including osteosarcomas, are sensitive to p53 restoration in preclinical experiments [97-100], sarcoma patients may also be good candidates for treatment with Ad-p53-based cancer gene therapy.”
BackgroundHyperthermia Selectively Targets Human Papillomavirus in Cervical Tumors via p53-Dependent Apoptosis
Oei, A. L., van Leeuwen, C. M., ten Cate, R., Rodermond, H. M., Buist, M. R., Stalpers, L. J. A., Crezee, J., Kok, H. P., Medema, J. P., & Franken, N. A. P. (2015) · Cancer Research · doi:10.1158/0008-5472.can-15-0816 · Cited by 62
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“mMT (26), ROSA26-Cre-ER (Cre-ER) (27), Tbx21 (28), Stat3 (29), Aicda-cre (30), ROSA26-YFP (31), and Ifng (32) mice were originally from the listed references.”
From structure to dynamics: Frequency tuning in the p53-Mdm2 network. II
Ouattara, D. A., Abou-Jaoudé, W., & Kaufman, M. (2010) · Journal of Theoretical Biology · doi:10.1016/j.jtbi.2010.03.031 · Cited by 61
“p53 is a key tumor suppressor protein that plays a major role in the control of the proliferation of genetically unstable cells (Ventura et al., 2007).”
BackgroundActivation of the aryl hydrocarbon receptor by TCDD inhibits senescence: A tumor promoting event?
Ray, S. S., & Swanson, H. I. (2008) · Biochemical Pharmacology · doi:10.1016/j.bcp.2008.11.022 · Cited by 62
“An example of such in vivo study includes use of a mouse model containing the same Ras transgene as that of the TgAC mice [59], but would also include an additional genetic modification to facilitate acute re-expression of p53 and induction of senescence [34,35].”
BackgroundGuo, H., Liu, Z., Xu, B., Hu, H., Wei, Z., Liu, Q., Zhang, X., Ding, X., Wang, Y., Zhao, M., et al. (2013) · Aging Cell · doi:10.1111/acel.12138 · Cited by 63
“While cellular senescence has been shown to depend on p53 in many experimental settings (Pearson et al., 2000; Schmitt et al., 2002; Chen et al., 2005; Ventura et al., 2007), only a few p53 target genes, namely p21, PAI-1, PML, and E2F7, are known to mechanistically contribute to cellular senescence (Brugarolas et al.”
BackgroundTalekar, M., Trivedi, M. S., Shah, P., Ouyang, Q., Oka, A., Gandham, S. K., & Amiji, M. M. (2015) · Molecular Therapy · doi:10.1038/mt.2015.225 · Cited by 63
Panigrahi, K., Eggen, M., Maeng, J.-H., Shen, Q., & Berkowitz, D. B. (2009) · Chemistry & Biology · doi:10.1016/j.chembiol.2009.08.008 · Cited by 61
“Jacks and coworkers developed a clever genetic construct for temporal control of p53 expression (Ventura et al., 2007).”
Chronic treatment with ginsenoside Rg3 induces Akt-dependent senescence in human glioma cells
Seong, S., Kim, S. Y., & Kim, S. S. (2012) · International Journal of Oncology · doi:10.3892/ijo.2012.1604 · Cited by 60
Acute DNA damage activates the tumour suppressor p53 to promote radiation-induced lymphoma
Lee, C., Castle, K. D., Moding, E. J., Blum, J. M., Williams, N. T., Luo, L., Ma, Y., Borst, L. B., Kim, Y., & Kirsch, D. G. (2015) · Nature Communications · doi:10.1038/ncomms9477 · Cited by 58
Self-citationAutophagy induced by p53-reactivating molecules protects pancreatic cancer cells from apoptosis
Fiorini, C., Menegazzi, M., Padroni, C., Dando, I., Pozza, E. D., Gregorelli, A., Costanzo, C., Palmieri, M., & Donadelli, M. (2012) · APOPTOSIS · doi:10.1007/s10495-012-0790-6 · Cited by 63
“In vivo studies performed in mice have shown that restoration of wild-type p53 function by various molecular approaches causes rapid tumor regression [7, 8].”
BackgroundAsara, Y., Marchal, J. A., Carrasco, E., Boulaiz, H., Solinas, G., Bandiera, P., García, M. Á., Farace, C., Montella, A., & Madeddu, R. (2013) · International Journal of Molecular Sciences · doi:10.3390/ijms140816600 · Cited by 60
“The effects of 5-FU on p53 expression are similar to those observed after tumour regression in vivo, demonstrating the therapeutic potential of reactivating p53 in established tumours [44–46].”
BackgroundTissue-specific p19 Arf regulation dictates the response to oncogenic K-ras
Young, N. P., & Jacks, T. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1004796107 · Cited by 59
“We generated triplemutant mice containing Arf, a recently constructed Flp recombinase-inducible K-ras allele (K-rasFSF-G12D), and a widely expressed tamoxifen-inducible allele of Cre, R26 (28).”
BackgroundSelf-citationIlluminating p53 function in cancer with genetically engineered mouse models
Garcia, P. B., & Attardi, L. D. (2014) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2013.12.014 · Cited by 65
Past, Present, and Future of Molecular and Cellular Oncology
Galluzzi, L., Vitale, I., & Kroemer, G. (2011) · Frontiers in Oncology · doi:10.3389/fonc.2011.00001 · Cited by 62
Wickremasinghe, R. G., Prentice, A., & Steele, A. J. (2011) · Leukemia · doi:10.1038/leu.2011.103 · Cited by 59
Acute Loss of Apolipoprotein E Triggers an Autoimmune Response That Accelerates Atherosclerosis
Centa, M., Prokopec, K. E., Garimella, M. G., Habir, K., Hofste, L., Stark, J. M., Dahdah, A., Tibbitt, C. A., Polyzos, K. A., Gisterå, A., et al. (2018) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.118.310802 · Cited by 59
Inhibition of Wild-Type p53-Expressing AML by the Novel Small Molecule HDM2 Inhibitor CGM097
Weisberg, E., Halilovic, E., Cooke, V. G., Nonami, A., Ren, T., Sanda, T., Simkin, I., Yuan, J., Antonakos, B., Barys, L., et al. (2015) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-15-0429 · Cited by 56
BCL9/9L-β-catenin Signaling is Associated With Poor Outcome in Colorectal Cancer
Moor, A. E., Anderle, P., Cantù, C., Rodriguez, P., Wiedemann, N., Baruthio, F., Deka, J., André, S., Valenta, T., Moor, M. B., et al. (2015) · EBioMedicine · doi:10.1016/j.ebiom.2015.10.030 · Cited by 58
“4-hydroxytamoxifen (4-OHT) exposure of intestinal organoids derived from of Apc/Kras mice expressing R26-CreERT (Ventura et al., 2007) and carrying Bcl9/9l alleles resulted in a rapid shift in the ratio between sphere-like and budding organoids, with progressive disappearance of spheroid structures over 48 h, whereas…”
BackgroundInfluentialBeyond knockouts: cre resources for conditional mutagenesis
Murray, S. A., Eppig, J. T., Smedley, D. P., Simpson, E. M., & Rosenthal, N. A. (2012) · Mammalian Genome · doi:10.1007/s00335-012-9430-2 · Cited by 58
“…a recombinase mediate cassette exchange (RMCE) docking site and has been successfully employed for loci, including Gt(ROSA)26Sor (Zambrowicz et al. 1997; Badea et al. 2003; Jullien et al. 2007; Raymond and Soriano 2007; Ventura et al. 2007), Hprt (Yang et al. 2009), and Hipp11 (Tasic et al. 2011).”
One Function—Multiple Mechanisms: The Manifold Activities of p53 as a Transcriptional Repressor
Böhlig, L., & Rother, K. (2011) · BioMed Research International · doi:10.1155/2011/464916 · Cited by 58
“p53 knockout mice are susceptible to different tumor types [5] and restoration of p53-function leads to the regression of tumors in vivo [6, 7].”
BackgroundCam, M., Bid, H. K., Xiao, L., Zambetti, G. P., Houghton, P. J., & Çam, H. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.530303 · Cited by 60
“To restore p53 protein, we used a well established p53-loxSTOP-lox (LSL) MEF model (26).”
MethodThe Role of Suppressors of Cytokine Signalling in Human Neoplasms
Sasi, W., Sharma, A. K., & Mokbel, K. (2014) · Molecular Biology International · doi:10.1155/2014/630797 · Cited by 60
Bolesta, E., Pfannenstiel, L. W., Demelash, A., Lesniewski, M. L., Tobin, M., Schlanger, S. E., Nallar, S. C., Papadimitriou, J. C., Kalvakolanu, D. V., & Gastman, B. (2012) · Molecular and Cellular Biology · doi:10.1128/mcb.06214-11 · Cited by 60
“Many tumors have inactive p53, which results in resistance to both apoptosis and senescence (5, 34).”
BackgroundThe mutant p53 mouse as a pre-clinical model
Jackson, J. G., & Lozano, G. (2013) · Oncogene · doi:10.1038/onc.2012.610 · Cited by 57
Cellular senescence: a double‐edged sword in the fight against cancer
Ohtani, N., Takahashi, A., Mann, D. J., & Hara, E. (2012) · Experimental Dermatology · doi:10.1111/j.1600-0625.2012.01493.x · Cited by 57
Using extracellular biomarkers for monitoring efficacy of therapeutics in cancer patients: an update
Beachy, S. H., & Repasky, E. A. (2008) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-007-0445-6 · Cited by 59
“Restoration of p53 leads to tumor regression primarily by apoptosis in lymphomas, and senescence, although delayed, in sarcomas [98].”
BackgroundWhen the guardian sleeps: Reactivation of the p53 pathway in cancer
Merkel, O., Taylor, N., Prutsch, N., Staber, P. B., Moriggl, R., Turner, S. D., & Kenner, L. (2017) · Mutation Research/Reviews in Mutation Research · doi:10.1016/j.mrrev.2017.02.003 · Cited by 56
“In murine models, reconfiguration of mutant p53 to its active WT function restores apoptosis and promotes retardation and even regression of advanced tumors (Martins, Brown-Swigart, & Evan, 2006; Ventura et al., 2007).”
Backgroundp53 Isoforms in Cellular Senescence- and Ageing-Associated Biological and Physiological Functions
Fujita, K. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20236023 · Cited by 59
“The acute activation of p53 in hepatocellular carcinomas and sarcomas induces senescence, which is followed by tumor elimination [133,134].”
BackgroundImaging Primary Lung Cancers in Mice to Study Radiation Biology
Kirsch, D. G., Grimm, J., Guimarães, A. R., Wojtkiewicz, G. R., Perez, B. A., Santiago, P. M., Anthony, N. K., Forbes, T., Doppke, K. P., Weissleder, R., et al. (2010) · International Journal of Radiation Oncology*Biology*Physics · doi:10.1016/j.ijrobp.2009.11.038 · Cited by 58
“In this system, spontaneous cancers develop in tumor-prone strains of mice (7,8).”
BackgroundSelf-citationTargeting the Ubiquitin-Mediated Proteasome Degradation of p53 for Cancer Therapy
DeVine, T., & Dai, M. (2013) · Current Pharmaceutical Design · doi:10.2174/1381612811319180009 · Cited by 58
E3 ubiquitin ligase Skp2 as an attractive target in cancer therapy
Hao, Z. (2015) · Frontiers in bioscience · doi:10.2741/4320 · Cited by 57
Othman, N., & Nagoor, N. H. (2014) · BioMed Research International · doi:10.1155/2014/318030 · Cited by 57
“p53 function has led to regression of cancers in mice [137, 138], and thus efforts to treat 459 cancers through the reactivation of p53 with a low-molecular-weight compound such as 460”
BackgroundSenescence and tumor suppression
Hinds, P. W., & Pietruska, J. R. (2017) · F1000Research · doi:10.12688/f1000research.11671.1 · Cited by 56
Smeets, M. F. M. A., Tan, S. Y., Xu, J. J., Anande, G., Unnikrishnan, A., Chalk, A. M., Taylor, S., Pimanda, J. E., Wall, M., Purton, L. E., et al. (2018) · Blood · doi:10.1182/blood-2018-04-845602 · Cited by 61
The Rad50 hook domain regulates DNA damage signaling and tumorigenesisPreprint
Roset, R., Inagaki, A., Hohl, M., Brenet, F. A., Lafrance‐Vanasse, J., Lange, J., Scandura, J. M., Tainer, J. A., Keeney, S., & Petrini, J. H. J. (2014) · Genes & Development · doi:10.1101/gad.236745.113 · Cited by 57
“Rad50+/46 and Rad50+/D mice were crossed with Rad50ind/ind (in which exons 1 and 2 are flanked by loxP sites) (Adelman et al. 2009) and a tamoxifen-inducible Cre (Ventura et al. 2007).”
BackgroundVaseva, A. V., Yallowitz, A. R., Marchenko, N. D., Xu, S., & Moll, U. M. (2011) · Cell Death & Disease · doi:10.1038/cddis.2011.39 · Cited by 55
“The concept of targeted reactivation of wtp53 for therapy is greatly strengthened by mouse models, where genetic restoration of p53 in established tumors leads to clinical tumor regression.(2,3) Thus, pharmacological strategies to induce p53 activation in human tumors carry high potential in cancer therapy.”
BackgroundZhao, M., Wang, T., Gleber‐Netto, F. O., Chen, Z., McGrail, D. J., Gomez, J. A., Ju, W., Gadhikar, M. A., Ma, W., Shen, L., et al. (2024) · Nature Communications · doi:10.1038/s41467-023-44239-2 · Cited by 63
TP53 dysfunction in diffuse large B-cell lymphoma
Lu, T., Young, K. H., Xu, W., & Li, J.-Y. (2015) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2015.08.006 · Cited by 58
Human recombinant arginase enzyme reduces plasma arginine in mouse models of arginase deficiency
Burrage, L. C., Sun, Q., Elsea, S. H., Jiang, M., Nagamani, S. C. S., Frankel, A. E., Stone, E. M., Alters, S. E., Johnson, D. E., Rowlinson, S. W., et al. (2015) · Human Molecular Genetics · doi:10.1093/hmg/ddv352 · Cited by 56
“129-Gt(ROSA)26Sor/J; Cre+) to generate an inducible adult mouse model of arginase deficiency (27,28,40,41).”
MethodThe molecular genetics of adrenocortical carcinoma
Barlaskar, F. M., & Hammer, G. D. (2007) · Reviews in Endocrine and Metabolic Disorders · doi:10.1007/s11154-007-9057-x · Cited by 56
WIP1 phosphatase as pharmacological target in cancer therapy
Pecháčková, S., Burdová, K., & Macůrek, L. (2017) · Journal of Molecular Medicine · doi:10.1007/s00109-017-1536-2 · Cited by 57
Using Mice to Examine p53 Functions in Cancer, Aging, and LongevityPreprint
Donehower, L. A. (2009) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a001081 · Cited by 59
“Subsequent studies by the Jacks and Lowe laboratories with inducible wild-type p53 mouse models showed that restoration of p53 function can cause dramatic tumor regression in part through induction of senescence (Ventura et al. 2007; Xue et al. 2007).”
BackgroundEffenberger, T., von der Heyde, J., Bartsch, K., Garbers, C., Schulze‐Osthoff, K., Chalaris, A., Murphy, G., Rose‐John, S., & Rabe, B. (2014) · The FASEB Journal · doi:10.1096/fj.14-254565 · Cited by 54
“On the one hand the SASP, mainly due to increased expression of cell adhesion molecules and chemokines, can facilitate removal of senescent cells by attracting phagocytic immune cells, which in turn clean up these potentially carcinogenic cells (5, 6).”
BackgroundSaiki, A. Y., Caenepeel, S., Yu, D., Lofgren, J. A., Osgood, T., Robertson, R., Canon, J., Su, C., Jones, A., Zhao, X., et al. (2014) · Oncotarget · doi:10.18632/oncotarget.1918 · Cited by 55
“In support of this hypothesis, three groups of investigators have used mouse models to demonstrate that absence of p53 function is a continuous requirement for the maintenance of established tumors [6-8].”
BackgroundRegulation of Senescence in Cancer and Aging
Kong, Y., Cui, H., Ramkumar, C., & Zhang, H. (2011) · Journal of Aging Research · doi:10.4061/2011/963172 · Cited by 61
Burgdorf, K. S., Grarup, N., Justesen, J. M., Harder, M. N., Witte, D. R., Jørgensen, T., Sandbæk, A., Lauritzen, T., Madsbad, S., Hansen, T. F., et al. (2011) · PLoS ONE · doi:10.1371/journal.pone.0015813 · Cited by 55
“TP53 encodes the tumor suppressor protein p53, which is known to be involved in cell-cycle control, apoptosis and maintenance of genetic stability, thereby protecting the organism from cellular damage [13].”
BackgroundTumor Angiogenesis in the Absence of Fibronectin or Its Cognate Integrin Receptors
Murphy, P. A., Begum, S., & Hynes, R. O. (2015) · PLoS ONE · doi:10.1371/journal.pone.0120872 · Cited by 56
Genetic blockade of lymphangiogenesis does not impair cardiac function after myocardial infarction
Keller, T. C. S., Lim, L. Y., Shewale, S. V., McDaid, K. S., Martí-Pàmies, Í., Tang, A. T., Wittig, C. F., Guerrero, A. A., Sterling, S., Leu, N. A., et al. (2021) · Journal of Clinical Investigation · doi:10.1172/jci147070 · Cited by 59
“The Prox1-CreERT2 385 (stock 022075) and the R26-CreERT2 (stock 008463) (41) mouse were purchased from 386”
Erratum: PRIMA-1Met induces mitochondrial apoptosis through activation of caspase-2
Shen, J., Vakifahmetoglu, H., Stridh, H., Zhivotovsky, B., & Wiman, K. G. (2016) · Oncogene · doi:10.1038/onc.2016.210 · Cited by 54
“This notion is supported by recent studies in mice showing that restoration of wild-type p53 expression in tumors in vivo has a significant antitumor effect, despite the presence of other genetic alterations (Ventura et al., 2007; Xue et al., 2007).”
ResultRetractedThe p53 tumor suppressor network in cancer and the therapeutic modulation of cell death
Chari, N. S., Pinaire, N. L., Thorpe, L., Medeiros, L. J., Routbort, M. J., & McDonnell, T. J. (2009) · APOPTOSIS · doi:10.1007/s10495-009-0327-9 · Cited by 54
“expression is a consequence of apoptosis, cellular senescence, or other mechanisms may be a function of the tissue and cell of origin [45].”
BackgroundZinc supplementation augments in vivo antitumor effect of chemotherapy by restoring p53 function
Margalit, O., Simon, A. J., Yakubov, E., Puca, R., Yosepovich, A., Avivi, C., Jacob‐Hirsch, J., Gelernter, I., Harmelin, A., Barshack, I., et al. (2011) · International Journal of Cancer · doi:10.1002/ijc.26441 · Cited by 58
T cell receptor and cytokine signal integration in CD8+ T cells is mediated by the protein Themis
Brzostek, J., Gautam, N., Zhao, X., Chen, E. W., Mehta, M., Tung, D. W. H., Chua, Y. L., Yap, J., Cho, S. H., Sankaran, S., et al. (2020) · Nature Immunology · doi:10.1038/s41590-019-0570-3 · Cited by 54
Consequences of NMDA Receptor Deficiency Can Be Rescued in the Adult Brain
Mielnik, C. A., Binko, M. A., Chen, Y., Funk, A. J., Johansson, E. M., Intson, K., Sivananthan, N., Islam, R., Milenkovic, M., Horsfall, W., et al. (2018) · Molecular Psychiatry · doi:10.1038/s41380-020-00859-4 · Cited by 56
Immune Surveillance of Unhealthy Cells by Natural Killer CellsPreprint
Iannello, A., & Raulet, D. H. (2013) · Cold Spring Harbor Symposia on Quantitative Biology · doi:10.1101/sqb.2013.78.020255 · Cited by 60
“…mediated by activation of p53/p21 and p16/Rb tumorsuppressor pathways, can trigger senescence by transactivating genes that arrest cell cycle progression and promote the senescent state (Serrano et al. 1997; Narita et al. 2003; Braig et al. 2005; Michaloglou et al. 2005; Ventura et al. 2007).”
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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