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.
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
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]
Citations
Cites
Hanahan, D., & Weinberg, R. A. (2000) · Cell · doi:10.1016/s0092-8674(00)81683-9 · Cited by 29,219
Lynch, T. J., Bell, D. W., Sordella, R., Gurubhagavatula, S., Okimoto, R. A., Brannigan, B. W., Harris, P. L., Haserlat, S. M., Supko, J. G., Haluska, F. G., et al. (2004) · New England Journal of Medicine · doi:10.1056/nejmoa040938 · Cited by 11,486
EGFR Mutations in Lung Cancer: Correlation with Clinical Response to Gefitinib Therapy
Paez, J. G., Jänne, P. A., Lee, J. C., Tracy, S., Greulich, H., Gabriel, S., Herman, P., Kaye, F. J., Lindeman, N., Boggon, T. J., et al. (2004) · Science · doi:10.1126/science.1099314 · Cited by 9,368
Generalized lacZ expression with the ROSA26 Cre reporter strain
Soriano, P. (1999) · Nature Genetics · doi:10.1038/5007 · Cited by 5,237
Druker, B. J., Talpaz, M., Resta, D. J., Peng, B., Buchdunger, E., Ford, J., Lydon, N., Kantarjian, H. M., Capdeville, R., Ohno-Jones, S., et al. (2001) · New England Journal of Medicine · doi:10.1056/nejm200104053441401 · Cited by 5,237
In Vivo Activation of the p53 Pathway by Small-Molecule Antagonists of MDM2
Vassilev, L. T., Vu, B. T., Graves, B., Carvajal, D., Podlaski, F., Filipovic, Z., Kong, N., Kammlott, U., Lukacs, C., Klein, C., et al. (2004) · Science · doi:10.1126/science.1092472 · Cited by 4,661
Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours
Donehower, L. A., Harvey, M., Slagle, B. L., McArthur, M. J., Montgomery, C. A., Butel, J. S., & Bradley, A. (1992) · Nature · doi:10.1038/356215a0 · Cited by 4,649
Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors
Demetri, G. D., von Mehren, M., Blanke, C. D., Van den Abbeele, A. D., Eisenberg, B., Roberts, P. J., Heinrich, M. C., Tuveson, D. A., Singer, S., Janicek, M., et al. (2002) · New England Journal of Medicine · doi:10.1056/nejmoa020461 · Cited by 4,389
Self-citationSenescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas
Xue, W., Zender, L., Miething, C., Dickins, R. A., Hernando, E., Krizhanovsky, V., Cordon-Cardo, C., & Lowe, S. W. (2007) · Nature · doi:10.1038/nature05529 · Cited by 2,473
Tumor spectrum analysis in p53-mutant mice
Jacks, T., Remington, L., Williams, B. O., Schmitt, E. M., Halachmi, S., Bronson, R. T., & Weinberg, R. A. (1994) · Current Biology · doi:10.1016/s0960-9822(00)00002-6 · Cited by 2,051
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Items 201–300 of 1,007
Etchin, J., Sanda, T., Mansour, M. R., Kentsis, A., Montero, J., Le, B. T., Christie, A. L., McCauley, D., Rodig, S. J., Kauffman, M. G., et al. (2013) · British Journal of Haematology · doi:10.1111/bjh.12231 · Cited by 182
“Therefore, CRM1 inhibition leads to the forced nuclear retention, upregulation, and activation of multiple TSPs. Restoration/reactivation of TSPs is known to selectively kill tumour cells (Martins et al, 2006; Ventura et al, 2007).”
BackgroundContext-dependent effects of cellular senescence in cancer development.
Lecot, P., Alimirah, F., Desprez, P.-Y., Campisi, J., & Wiley, C. (2016) · British Journal of Cancer · doi:10.1038/bjc.2016.115 · Cited by 183
“In addition to its beneficial role in wound healing, senescent cells recruit innate immune cells to kill tumour cells (Ventura et al, 2007; Xue et al, 2007).”
BackgroundSenescence promotes in vivo reprogramming through p16INK4a and IL‐6
Mosteiro, L., Pantoja, C., de Martino, A., & Serrano, M. (2018) · Aging Cell · doi:10.1111/acel.12711 · Cited by 182
“…suggest that during in vivo reprogramming p21 protein levels are regulated post-transcriptionally, possibly through one or some of the multiple post-transcriptional mechanisms that are known to regulate p21 (Scoumanne, Cho, Zhang & Chen, 2011; Warfel & El-Deiry, 2013; Zhang & Chen, 2008).”
BackgroundThe MYCN Protein in Health and Disease
Ruiz-Pérez, M. V., Henley, A. B., & Arsenian‐Henriksson, M. (2017) · Genes · doi:10.3390/genes8040113 · Cited by 191
“The restoration of p53 has been linked to tumor regression and due to apoptosis and cell growth suppression [160].”
Zhou, X., Singh, M., Sanz Santos, G., Guerlavais, V., Carvajal, L. A., Aivado, M., Zhan, Y., Oliveira, M. M. S., Westerberg, L. S., Annis, D. A., et al. (2021) · Cancer Discovery · doi:10.1158/2159-8290.cd-20-1741 · Cited by 169
“Reinstatement of the major tumor suppressor p53 by genetic means have demonstrated remarkable tumor suppression in animal models, providing strong support for p53 reactivation as a promising anti-cancer strategy (1-3).”
BackgroundMutant p53 reactivation by small molecules makes its way to the clinic
Bykov, V. J. N., & Wiman, K. G. (2014) · FEBS Letters · doi:10.1016/j.febslet.2014.04.017 · Cited by 181
“Several studies have shown that reconstitution of wild type p53 expression by various means in mice induces rapid tumor regression [14–16].”
BackgroundHutchinson, M.-K. N. D., Mierzwa, M. L., & D’Silva, N. J. (2020) · Oncogene · doi:10.1038/s41388-020-1250-3 · Cited by 197
Tissue-specific and reversible RNA interference in transgenic mice
Dickins, R. A., McJunkin, K., Hernando, E., Premsrirut, P. K., Krizhanovsky, V., Burgess, D. J., Kim, S. Y., Cordon-Cardo, C., Zender, L., Hannon, G. J., et al. (2007) · Nature Genetics · doi:10.1038/ng2045 · Cited by 174
“Our results are generally consistent with recent studies from our group and other group”
Viatour, P., Somervaille, T. C., Venkatasubrahmanyam, S., Kogan, S., McLaughlin, M. E., Weissman, I. L., Butte, A. J., Passegué, E., & Sage, J. (2008) · Cell Stem Cell · doi:10.1016/j.stem.2008.07.009 · Cited by 178
“To bypass this problem, we crossed condTKO mice to Rosa26Cre-ERT2 mice (Ventura et al., 2007).”
Self-citationp53 Regulation of Metabolic PathwaysPreprint
Gottlieb, E., & Vousden, K. H. (2009) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a001040 · Cited by 189
“Genotoxic damage, oncogene activation, telomere erosion, loss of stromal support, and nutrient and oxygen deprivation can all activate p53 (Horn and Vousden 2007), resulting in the induction of apoptotic cell death or senescence—two responses that irreversibly remove the cell from the proliferative…”
BackgroundMAX and MYC: A Heritable Breakup
Cascón, A., & Robledo, M. (2012) · Cancer Research · doi:10.1158/0008-5472.can-11-3891 · Cited by 184
“Nevertheless, strategies to restore protein function are now considered viable anticancer therapeutic approaches (36), and thus may be an option for MAX-related PCCs that have a potentially malignant phenotype.”
BackgroundLee, J.-J., Kim, B. C., Park, M.-J., Lee, Y., Kim, Y.-N., Lee, B. L., & Js, L. (2010) · Cell Death and Differentiation · doi:10.1038/cdd.2010.139 · Cited by 179
“In addition, as cellular senescence is abundant in premalignant neoplastic lesions and tumor regression is attributed to cellular senescence, this process is considered to have a crucial role in tumor treatment.(18,19) Indeed, if cellular senescence pathways remain intact, senescence induction could compensate for the…”
BackgroundAdams, P. D. (2007) · Gene · doi:10.1016/j.gene.2007.04.020 · Cited by 182
RNAa Is Conserved in Mammalian Cells
Huang, V., Qin, Y., Wang, J., Wang, X., Place, R. F., Lin, G., Lue, T. F., & Li, L.-C. (2010) · PLoS ONE · doi:10.1371/journal.pone.0008848 · Cited by 174
“For instance, restoration of p53 function has recently been shown to cause dramatic tumor regression in mice [19,20,21].”
BackgroundTRIM59 Is Up-regulated in Gastric Tumors, Promoting Ubiquitination and Degradation of p53
Zhou, Z., Ji, Z., Wang, Y., Li, J., Cao, H., Zhu, H. H., & Gao, W. (2014) · Gastroenterology · doi:10.1053/j.gastro.2014.07.021 · Cited by 170
The Eph-Receptor A7 Is a Soluble Tumor Suppressor for Follicular Lymphoma
Oricchio, E., Nanjangud, G. J., Wolfe, A. L., Schatz, J. H., Mavrakis, K. J., Jiang, M., Liu, X., Bruno, J., Heguy, A., Olshen, A. B., et al. (2011) · Cell · doi:10.1016/j.cell.2011.09.035 · Cited by 181
Protein Amounts of the MYC Transcription Factor Determine Germinal Center B Cell Division Capacity
Finkin, S., Hartweger, H., Oliveira, T. Y., Kara, E. E., & Nussenzweig, M. C. (2019) · Immunity · doi:10.1016/j.immuni.2019.06.013 · Cited by 179
Walle, L. V., Stowe, I. B., Šácha, P., Lee, B. L., Demon, D., Fossoul, A., Hauwermeiren, F. V., Saavedra, P. H. V., Šimon, P., Šubr, V., et al. (2019) · PLoS Biology · doi:10.1371/journal.pbio.3000354 · Cited by 172
“To this end, mice that were homozygous for the Nlrp3L351P allele were bred to transgenic mice that hemizygously expressed the tamoxifen-inducible Cre-ERT2 fusion gene (CreT) (Ventura et al., 2007).”
Senescence Regulation by the p53 Protein Family
Qian, Y., & Chen, X. (2012) · Methods in molecular biology · doi:10.1007/978-1-62703-239-1_3 · Cited by 181
Ceramide Glycosylation Catalyzed by Glucosylceramide Synthase and Cancer Drug Resistance
Liu, Y., Hill, R. A., & Li, Y. (2013) · Advances in cancer research · doi:10.1016/b978-0-12-394274-6.00003-0 · Cited by 171
“Restoration of wild-type p53 function has succeeded in bringing about regression of tumors, and in fact, this represents a promising approach for treating cancers (Brosh and Rotter, 2009; Ventura et al., 2007).”
BackgroundPeng, X., Zhang, M.-Q.-Z., Conserva, F., Hosny, G., Selivanova, G., Bykov, V. J. N., Arnér, E. S. J., & Wiman, K. G. (2013) · Cell Death & Disease · doi:10.1038/cddis.2013.417 · Cited by 170
The role of ubiquitin modification in the regulation of p53
Hock, A. K., & Vousden, K. H. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2013.05.022 · Cited by 168
Mechanosensing by β1 integrin induces angiocrine signals for liver growth and survival
Lorenz, L., Axnick, J., Buschmann, T., Henning, C., Urner, S., Fang, S., Nurmi, H., Eichhorst, N., Holtmeier, R., Bódis, K., et al. (2018) · Nature · doi:10.1038/s41586-018-0522-3 · Cited by 171
“Animals and other organisms Policy information about studies involving animals; ARRIVE guidelines recommended for reporting animal research Laboratory animals C57BL/6J (Janvier), Flk1-Cre (Licht et al., 2004), Cdh5-CreERT2 (Benedito et al., 2009), Itgb1-loxP (Potocnik, et al., 2000), Rosa26CreERT2 (Ventura et al., 200…”
BackgroundThe Structure‐Based Design of Mdm2/Mdmx–p53 Inhibitors Gets Serious
Popowicz, G. M., Dömling, A. S. S., & Holak, T. A. (2011) · Angewandte Chemie International Edition · doi:10.1002/anie.201003863 · Cited by 170
Rapid and tunable method to temporally control gene editing based on conditional Cas9 stabilization
Şentürk, Ş., Shirole, N. H., Nowak, D. G., Corbo, V., Pal, D., Vaughan, A., Tuveson, D. A., Trotman, L. C., Kinney, J. B., & Sordella, R. (2017) · Nature Communications · doi:10.1038/ncomms14370 · Cited by 175
“…include the generation of temperature-sensitive mutants 30 , conditional deletion alleles in which a gene of interest is flanked by loxP recombination sites to enable acute gene inactivation on expression of Cre recombinase 31 , and inducible gene knockdown based on shRNA mediated silencing 32 .”
Self-citationStructure-Based Design of Novel Inhibitors of the MDM2–p53 Interaction
Rew, Y., Sun, D., de Turiso, F. G.-L., Bartberger, M. D., Beck, H. P., Canon, J. R., Chen, A., Chow, D. T., Deignan, J., Fox, B. M., et al. (2012) · Journal of Medicinal Chemistry · doi:10.1021/jm300354j · Cited by 170
Normal stem cells and cancer stem cells: similar and different
Shackleton, M. J. (2010) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2010.04.002 · Cited by 168
Epithelial‐mesenchymal transition in cancer metastasis through the lymphatic system
Karlsson, M. C. I., González, S., Welin, J., & Fuxe, J. (2017) · Molecular Oncology · doi:10.1002/1878-0261.12092 · Cited by 159
“, 2011), and the oncogenic transformation and tumor regression in vivo (Ventura et al., 2007).”
BackgroundVEGFR3 Modulates Vascular Permeability by Controlling VEGF/VEGFR2 Signaling
Heinolainen, K., Karaman, S., D’Amico, G., Tammela, T., Sormunen, R. T., Eklund, L., Alitalo, K. K., & Zarkada, G. (2017) · Circulation Research · doi:10.1161/circresaha.116.310477 · Cited by 170
Recent Advances in Anti-cancer Protein/Peptide Delivery
Liu, X., Wu, F., Ji, Y. I., & Yin, L. (2018) · Bioconjugate Chemistry · doi:10.1021/acs.bioconjchem.8b00750 · Cited by 163
The UHRF family: Oncogenes that are drugable targets for cancer therapy in the near future?
Bronner, C., Achour, M., Arima, Y., Chataigneau, T., Saya, H., & Schini‐Kerth, V. B. (2007) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2007.06.003 · Cited by 160
Cell size is a determinant of stem cell potential during aging
Lengefeld, J., Cheng, C., Maretich, P., Blair, M., Hagen, H. R., McReynolds, M. R., Sullivan, E. J., Majors, K., Roberts, C., Kang, J. H., et al. (2021) · Science Advances · doi:10.1126/sciadv.abk0271 · Cited by 165
Current strategies to target p53 in cancer
Chen, F., Wang, W., & El‐Deiry, W. S. (2010) · Biochemical Pharmacology · doi:10.1016/j.bcp.2010.04.031 · Cited by 158
“demonstrated inactivation of p53 was indeed a necessary component inmaintaining tumor phenotype as all three studies had showed that restoring p53 alone was sufficient to induce tumor regression in mice [13–15].”
p53 Activates the Long Noncoding RNA Pvt1b to Inhibit Myc and Suppress Tumorigenesis
Olivero, C. E., Martínez‐Terroba, E., Zimmer, J. T., Liao, C., Tesfaye, E., Hooshdaran, N., Schofield, J. A., Bendor, J., Fang, D., Simon, M. D., et al. (2020) · Molecular Cell · doi:10.1016/j.molcel.2019.12.014 · Cited by 159
Wild-Type p53: Tumors Can't Stand It
Kastan, M. B. (2007) · Cell · doi:10.1016/j.cell.2007.02.022 · Cited by 158
Current developments of targeting the p53 signaling pathway for cancer treatment
Huang, J. L. (2020) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2020.107720 · Cited by 157
Telomerase, senescence and ageing
Shawi, M., & Autexier, C. (2008) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2007.11.007 · Cited by 160
“…et al., 2006; Ventura et al., 2007; Xue et al., 2007). p53 activation allowed the regression of spontaneous or irradiationinduced sarcomas and lymphomas in only 2 days (Ventura et al., 2007), whereas, almost complete regression of hepatocarcinomas was observed in 12 days (Xue et al., 2007).”
InfluentialCaspase-2-Mediated Cleavage of Mdm2 Creates a p53-Induced Positive Feedback Loop
Oliver, T. G., Meylan, E., Chang, G. P., Xue, W., Burke, J. R., Humpton, T. J., Hubbard, D., Bhutkar, A. J., & Jacks, T. (2011) · Molecular Cell · doi:10.1016/j.molcel.2011.06.012 · Cited by 163
“We next took advantage of a unique mouse model system that allows restoration of endogenous p53 to physiological levels (Ventura et al., 2007).”
BackgroundSelf-citationAging by epigenetics—A consequence of chromatin damage?
Sedivy, J. M., Gowrishankar, B., & Adams, P. D. (2008) · Experimental Cell Research · doi:10.1016/j.yexcr.2008.02.023 · Cited by 159
“senescence phenotype, they might primarily contribute to senescence-mediated tumor suppression [81–87].”
BackgroundShould mutant TP53 be targeted for cancer therapy?
Wang, Z., Strasser, A., & Kelly, G. L. (2022) · Cell Death and Differentiation · doi:10.1038/s41418-022-00962-9 · Cited by 162
Classical and Novel Prognostic Markers for Breast Cancer and their Clinical Significance
Taneja, P., Maglic, D., Kai, F., Zhu, S., Kendig, R. D., Elizabeth, A., & Inoue, K. (2010) · Clinical Medicine Insights Oncology · doi:10.4137/cmo.s4773 · Cited by 160
Precise targeting of POLR2A as a therapeutic strategy for human triple negative breast cancer
Xu, J., Liu, Y., Li, Y., Wang, H., Stewart, S., der Jeught, K. V., Agarwal, P., Zhang, Y., Liu, S., Zhao, G., et al. (2019) · Nature Nanotechnology · doi:10.1038/s41565-019-0381-6 · Cited by 153
Liikanen, I., Lauhan, C. R., Quon, S., Omilusik, K. D., Phan, A. T., Bartrolí, L. B., Ferry, A., Goulding, J., Chen, J., Scott-Browne, J. P., et al. (2021) · Journal of Clinical Investigation · doi:10.1172/jci143729 · Cited by 160
“either dLck-Cre mice (61) or to Rosa26Cre-ERT2 (ER-Cre) mice (62) fol-”
BackgroundPitx2 modulates a Tbx5 -dependent gene regulatory network to maintain atrial rhythm
Nadadur, R. D., Broman, M., Boukens, B. J., Mazurek, S. R., Yang, X. H., van den Boogaard, M., Bekeny, J. C., Gadek, M., Ward, T. L., Zhang, M., et al. (2016) · Science Translational Medicine · doi:10.1126/scitranslmed.aaf4891 · Cited by 152
“Adult-specific Tbx5 deletion causes rapid-onset AF Tbx5 was deleted from the adult mouse by combining a Tbx5 floxed allele (Tbx5) (5) with a tamoxifen (TM)–inducible Cre recombinase allele at the Rosa26 (R26) locus (14).”
BackgroundTargeting MDM2-p53 Interaction for Cancer Therapy: Are We There Yet?
Nag, S. A., Zhang, X., Srivenugopal, K. S., Wang, M.-H., Wang, W., & Zhang, R. (2014) · Current Medicinal Chemistry · doi:10.2174/09298673113206660325 · Cited by 156
The regulation of cellular metabolism by tumor suppressor p53
Liang, Y., Liu, J., & Feng, Z. (2013) · Cell & Bioscience · doi:10.1186/2045-3701-3-9 · Cited by 154
“Recent studies have shown that reactivation of p53 in tumors leads to the tumor regression in animal models, which provide further evidence that p53 can be targeted for cancer therapy [87,88].”
BackgroundOncogene- and tumor suppressor gene-mediated suppression of cellular senescence
Larsson, L. (2011) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2011.10.005 · Cited by 152
Pharmacologic Activation of p53 by Small-Molecule MDM2 Antagonists
Shen, H., & Maki, C. G. (2011) · Current Pharmaceutical Design · doi:10.2174/138161211795222603 · Cited by 148
The importance of p53 pathway genetics in inherited and somatic cancer genomes
Stracquadanio, G., Wang, X., Wallace, M. D., Grawenda, A. M., Zhang, P., Hewitt, J., Zerón-Medina-Cuairán, J., Castro-Giner, F., Tomlinson, I. P. M., Goding, C. R., et al. (2016) · Nature reviews. Cancer · doi:10.1038/nrc.2016.15 · Cited by 143
“…are consistent with the well-defined roles of the p53 stress response pathway in tumor suppression, regulating cell migration and invasion and mediating the cellular response to DNA damage-inducing cancer therapies, primarily mediated through the ability of p53 to regulate transcription 32–36 .”
Selection against PUMA Gene Expression in Myc-Driven B-Cell Lymphomagenesis
Garrison, S. P., Jeffers, J. R., Yang, C., Nilsson, J. A., Hall, M. A., Rehg, J. E., Yue, W., Yu, J., Zhang, L., Onciu, M. M., et al. (2008) · Molecular and Cellular Biology · doi:10.1128/mcb.00907-07 · Cited by 151
“Based upon these findings, we speculate that in the absence of Puma, p53 still becomes activated in response to deregulated c-Myc expression and suppresses the development of emerging lymphoma cells, no longer principally through the regulation of apoptosis but by blocking cell proliferation and/or inducing cell senes…”
BackgroundCarugo, A., Genovese, G., Seth, S., Nezi, L., Rose, J. L., Bossi, D., Cicalese, A., Shah, P. K., Viale, A., Pettazzoni, P., et al. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.05.063 · Cited by 140
“The pSICO and pSICO-Flpo were made by Dr. Tyler Jacks (Ventura et al., 2007).”
Systematic Mutational Analysis of Peptide Inhibition of the p53–MDM2/MDMX Interactions
Li, C. V., Pazgier, M., Li, C., Yuan, W., Liu, M., Wei, G., Lu, W., & Lu, W. (2010) · Journal of Molecular Biology · doi:10.1016/j.jmb.2010.03.005 · Cited by 149
p53 activates transcription by directing structural shifts in Mediator
Meyer, K. D., Lin, S., Bernecky, C., Gao, Y., & Taatjes, D. J. (2010) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.1816 · Cited by 157
“Because even transient reactivation of p53 can cause tumor regressio”
BackgroundAkt as a target for cancer therapy: more is not always better (lessons from studies in mice)
Wang, Q., Chen, X., & Hay, N. (2017) · British Journal of Cancer · doi:10.1038/bjc.2017.153 · Cited by 143
Oncogenic KrasG12D causes myeloproliferation via NLRP3 inflammasome activation
Hamarsheh, S., Oßwald, L., Saller, B. S., Unger, S., Feo, D. D., Vinnakota, J. M., Konantz, M., Uhl, F. M., Becker, H., Lübbert, M., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-15497-1 · Cited by 144
Opportunities for improving the therapeutic ratio for patients with sarcoma
Wunder, J. S., Nielsen, T. O., Maki, R. G., O’Sullivan, B., & Alman, B. A. (2007) · The Lancet Oncology · doi:10.1016/s1470-2045(07)70169-9 · Cited by 144
Mutant p53 stimulates chemoresistance of pancreatic adenocarcinoma cells to gemcitabine
Fiorini, C., Cordani, M., Padroni, C., Blandino, G., Agostino, S. D., & Donadelli, M. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2014.10.003 · Cited by 151
Efeyan, A., Ortega-Molina, A., Velasco-Miguel, S., Herranz, D., Vassilev, L. T., & Serrano, M. (2007) · Cancer Research · doi:10.1158/0008-5472.can-07-0200 · Cited by 140
“tumor senescence by p53 is followed by clearance of the senescent cells by the innate immune system, which results in tumor regression (30, 31 ).”
BackgroundTherapeutic Targeting of Telomerase
Jäger, K., & Walter, M. (2016) · Genes · doi:10.3390/genes7070039 · Cited by 144
“On one hand, both telomere-driven replicative senescence and stress-inducible senescence are tumor-suppressive [241–247].”
BackgroundPuca, R., Nardinocchi, L., Givol, D., & D’Orazi, G. (2010) · Oncogene · doi:10.1038/onc.2010.183 · Cited by 141
Pharmacological reactivation of mutant p53: from protein structure to the cancer patient
Wiman, K. G. (2010) · Oncogene · doi:10.1038/onc.2010.188 · Cited by 148
“This notion is strongly supported by in vivo studies showing that restoration of wild-type p53 function by various means in mice causes rapid tumor regression in vivo (Martins et al., 2006; Ventura et al., 2007; Xue et al., 2007).”
BackgroundGowrishankar, B., Somaiah, N., Zhang, R., Tang, Y., Hoffmann, J., Andrake, M., Ceulemans, H., Schultz, D., Marmorstein, R., & Adams, P. D. (2008) · Molecular and Cellular Biology · doi:10.1128/mcb.01047-08 · Cited by 156
“Cellular senescence is a known tumor suppressor mechanism (7, 8, 10, 11, 13, 17, 33, 52, 56, 62, 65) and is implicated in tissue aging (8, 28, 30, 34).”
BackgroundDavis, F. M., Lloyd‐Lewis, B., Harris, O. B., Kozar, S., Winton, D. J., Mureşan, L., & Watson, C. J. (2016) · Nature Communications · doi:10.1038/ncomms13053 · Cited by 138
Targeting ubiquitin specific proteases for drug discovery
Daviet, L., & Colland, F. (2008) · Biochimie · doi:10.1016/j.biochi.2007.09.013 · Cited by 126
Bykov, V. J. N., Zhang, Q., Zhang, M., Ceder, S., Abrahmsen, L., & Wiman, K. G. (2016) · Frontiers in Oncology · doi:10.3389/fonc.2016.00021 · Cited by 137
“Biochem Pharmacol (2012) 84(12):1563–70.”
Inhibition of p53 inhibitors: progress, challenges and perspectives
Sanz, G., Singh, M., Peuget, S., & Selivanova, G. (2019) · Journal of Molecular Cell Biology · doi:10.1093/jmcb/mjz075 · Cited by 140
“Studies taking advantage of mouse strains expressing ‘switchable’ p53 genes have uncovered a crucial role of p53 reconstitution in regression of already established tumors—lymphomas, soft tissue sarcomas, and hepatocellular carcinomas (Martins et al., 2006; Ventura et al., 2007; Xue et al., 2007).”
BackgroundWu, S., Ying, G., Wu, Q., & Capecchi, M. R. (2008) · Nature Protocols · doi:10.1038/nprot.2008.70 · Cited by 133
“Conditional rescue alleles can be equally informative if designed wel”
BackgroundLaine, A., Sihto, H., Come, C., Rosenfeldt, M. T., Zwolinska, A., Niemelä, M., Khanna, A., Chan, E. K., Kähäri, V.-M., Kellokumpu-Lehtinen, P.-L., et al. (2013) · Cancer Discovery · doi:10.1158/2159-8290.cd-12-0292 · Cited by 130
“Immunohistochemical staining for Ki–67 and DcR2 and hematoxylin and eosin (H&E) staining were conducted as previously described (41).”
BackgroundInfluentialGuo, M., Price, M. J., Patterson, D. G., Barwick, B. G., Haines, R. R., Kania, A. K., Bradley, J., Randall, T. D., Boss, J. M., & Scharer, C. D. (2017) · The Journal of Immunology · doi:10.4049/jimmunol.1701470 · Cited by 139
“To determine the role of Ezh2 in vivo, we crossed Ezh2 mice (31) with tamoxifen-inducible Rosa26 mice (32).”
BackgroundInfluentialCui, Y. R., & Guo, G. (2016) · International Journal of Molecular Sciences · doi:10.3390/ijms17111942 · Cited by 137
“In fact, genetic manipulations using mouse models demonstrated that p53 reactivation in p53-deficient tumors induced tumor apoptosis and/or senescence, which resulted in recruitment and activation of innate immune cells, including NK cells and macrophages, for the clearance of the apoptotic or senescent tumor cells [3…”
BackgroundTang, X., Zhu, Y., Han, L., Kim, A. L., Kopelovich, L., Bickers, D. R., & Athar, M. (2007) · Journal of Clinical Investigation · doi:10.1172/jci32481 · Cited by 138
Cellular senescence and cancer chemotherapy resistance
Gordon, R. R., & Nelson, P. S. (2012) · Drug Resistance Updates · doi:10.1016/j.drup.2012.01.002 · Cited by 138
“In cell based assays the artificial activation of p53 triggered tumor-specific apoptosis and senescence (Ventura et al., 2007).”
BackgroundLiu, Y., Wang, X., Wang, G., Yang, Y., Yuan, Y., & Ouyang, L. (2019) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2019.05.018 · Cited by 133
Peng, X., Zhang, M., Conserva, F., Hosny, G., Selivanova, G., Bykov, V. J. N., Arnér, E. S. J., & Wiman, K. G. (2017) · Cell Death and Disease · doi:10.1038/cddis.2016.137 · Cited by 134
Loss of Fbw7 Reprograms Adult Pancreatic Ductal Cells into α, δ, and β Cells
Sancho, R., Gruber, R., Gu, G., & Behrens, A. (2014) · Cell stem cell · doi:10.1016/j.stem.2014.06.019 · Cited by 133
The missing Zinc: p53 misfolding and cancer
Loh, S. N. (2010) · Metallomics · doi:10.1039/c003915b · Cited by 137
mTORC1 is essential for leukemia propagation but not stem cell self-renewal
Hoshii, T., Tadokoro, Y., Naka, K., Ooshio, T., Muraguchi, T., Sugiyama, N., Soga, T., Araki, K., Yamamura, K., & Hirao, A. (2012) · Journal of Clinical Investigation · doi:10.1172/jci62279 · Cited by 140
“Mice with the Raptorfl allele were crossed with Rosa26-CreERT2 mice (52) obtained from Tyler Jacks (Massachusetts Institute of Tech-”
Wang, Y., Suh, Y., Fuller, M. Y., Jackson, J. G., Xiong, S., Terzian, T., Quintás‐Cardama, A., Bankson, J. A., El‐Naggar, A. K., & Lozano, G. (2011) · Journal of Clinical Investigation · doi:10.1172/jci44504 · Cited by 137
Synthetic vulnerabilities of mesenchymal subpopulations in pancreatic cancer
Genovese, G., Carugo, A., Tepper, J., Robinson, F. S., Li, L., Svelto, M., Nezi, L., Corti, D., Minelli, R., Pettazzoni, P., et al. (2017) · Nature · doi:10.1038/nature21064 · Cited by 131
“In addition, we introduced a tamoxifen-inducible Cre recombinase (CreERT2) that is expressed in virtually all tissues 30 .”
InfluentialIAPP-driven metabolic reprogramming induces regression of p53-deficient tumours in vivo
Venkatanarayan, A., Raulji, P., Norton, W., Chakravarti, D., Coarfa, C., Su, X., Sandur, S. K., Ramirez, M. S., Lee, J., Kingsley, C. V., et al. (2014) · Nature · doi:10.1038/nature13910 · Cited by 132
Molecular Basis for the Inhibition of p53 by Mdmx
Popowicz, G. M., Czarna, A., Rothweiler, U., Szwagierczak, A., Krajewski, M., Weber, L., & Holak, T. A. (2007) · Cell Cycle · doi:10.4161/cc.6.19.4740 · Cited by 131
Small molecular weight protein–protein interaction antagonists—an insurmountable challenge?
Dömling, A. S. S. (2008) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2008.04.603 · Cited by 128
Tumor suppressor p53 and its gain-of-function mutants in cancer
Liu, J., Zhang, C., & Feng, Z. (2013) · Acta Biochimica et Biophysica Sinica · doi:10.1093/abbs/gmt144 · Cited by 133
“In mouse models, re-introduction of wild-type p53 into p53-deficient tumors leads to tumor regression [26,97], whereas reintroduction of wild-type p53 into mutant p53-harboring tumors suppresses tumor growth [98].”
DOT1L as a therapeutic target for the treatment of DNMT3A-mutant acute myeloid leukemia
Rau, R. E., Rodriguez, B. A. T., Luo, M., Jeong, M., Rosen, A., Rogers, J. H., Campbell, C. T., Daigle, S. R., Deng, L., Song, Y., et al. (2016) · Blood · doi:10.1182/blood-2015-11-684225 · Cited by 131
“2 Dnmt3a andDnmt3a were crossed to Rosa26-Cre ER.(26)Dnmt3aRosa26-Cre ER andDnmt3a-Rosa26-Cre ER mice were treated with 5 daily intraperitoneal injections of tamoxifen (1 mg/0.”
MethodThe isolation of an RNA aptamer targeting to p53 protein with single amino acid mutation
Chen, L., Rashid, F., Shah, A., Awan, H. M., Wu, M., Liu, A., Wang, J., Zhu, T., Luo, Z., & Shan, G. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1502159112 · Cited by 126
Smg6/Est1 licenses embryonic stem cell differentiation via nonsense‐mediated mRNA decay
Li, T., Shi, Y. X., Wang, P., Guachalla, L. M., Sun, B., Jörß, T., Chen, Y., Groth, M., Krueger, A., Platzer, M., et al. (2015) · The EMBO Journal · doi:10.15252/embj.201489947 · Cited by 128
“To substantiate this unexpected viability of Smg6 Δ / Δ ESCs, we crossed the Smg6 +/F mice with CreER T2 mice (Ventura et al , 2007) (Supplementary Fig S1C) and isolated Smg6 F/F ;CreER + (designated Smg6-CER) ESCs from the blastocysts derived from the intercrossing of Smg6 +/F ;CreER + mice…”
New insights into p53 activation
Brooks, C. L., & Gu, W. (2010) · Cell Research · doi:10.1038/cr.2010.53 · Cited by 102
“Reactivation of p53 in several mouse tumor models has been shown to be a potent inhibitor of tumor growth [83–85].”
BackgroundRan, L., Sirota, I., Cao, Z., Murphy, D. A., Chen, Y., Shukla, S., Xie, Y., Kaufmann, M. C., Gao, D., Zhu, S., et al. (2015) · Cancer Discovery · doi:10.1158/2159-8290.cd-14-0985 · Cited by 127
Zhang, D., Li, Y., Heims-Waldron, D. A., Bezzerides, V. J., Guatimosim, S., Guo, Y., Gu, F., Zhou, P., Lin, Z., Ma, Q., et al. (2017) · Circulation Research · doi:10.1161/circresaha.117.311349 · Cited by 131
Bmi-1: At the crossroads of physiological and pathological biology
Bhattacharya, R., Mustafi, S. B., Street, M., Dey, A., & Dwivedi, S. K. D. (2015) · Genes & Diseases · doi:10.1016/j.gendis.2015.04.001 · Cited by 132
“The cell cycle checkpoint that involves the Ink4a/Arf-p53-pRb axis has been described as the principle barrier to the initiation and maintenance of neoplastic transformation.(65,66) In contrast, a few studies have also reported that the proto-oncogene Bmi-1 is required for hepatocellular carcinoma (HCC) cell prolifera…”
BackgroundClassic and novel roles of p53: prospects for anticancer therapy
Fuster, J. J., Sanz-Gonzalez, S. M., Moll, U. M., & Andrés, V. (2007) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2007.03.002 · Cited by 128
“First, while p53 reactivation promotes tumor regression in the mouse [55-57], it might favor the growth of p53-resistant tumors carrying inactivating mutations in components of the p53 pathway, as shown”
BackgroundFrom structure to dynamics: Frequency tuning in the p53–Mdm2 network
Abou-Jaoudé, W., Ouattara, D. A., & Kaufman, M. (2009) · Journal of Theoretical Biology · doi:10.1016/j.jtbi.2009.02.005 · Cited by 124
Chen, J., & Kastan, M. B. (2010) · Genes & Development · doi:10.1101/gad.1968910 · Cited by 127
“A theoretical concern for blunting p53 induction in such settings might be the possibility of enhanced secondary tumors, but recent data suggest that restoration of p53 function to premalignant or malignant cells is sufficient to provide anti-tumor effects (Martins et al. 2006; Kastan 2007; Ventura et al. 2007; Xue et…”
FoxO transcription factors suppress Myc-driven lymphomagenesis via direct activation of ArfPreprint
Bouchard, C., Lee, S., Paulus-Hock, V., Loddenkemper, C., Eilers, M., & Schmitt, C. A. (2007) · Genes & Development · doi:10.1101/gad.453107 · Cited by 135
“Our data also provide a potential mechanistic link to recent elegant work from several laboratories using conditional alleles of p53, demonstrating that restoration of p53 in established tumors induces tumor regression in a manner that depends on p19, but not on the presence of acute DNA damage (Martins et al. 2006; V…”
BackgroundEXPRESSION OF CONCERN: Functional p53 determines docetaxel sensitivity in prostate cancer cells
Liu, C., Zhu, Y., Lou, W., Nadiminty, N., Chen, X., Zhou, Q., Shi, X., White, R. D., & Gao, A. C. (2012) · The Prostate · doi:10.1002/pros.22583 · Cited by 126
“p53 status has an important relationship with cancers, restoring endogenous p53 expression leads to regression of autochthonous lymphomas and sarcomas in mice without affecting normal tissues [39].”
BackgroundRetractedHeraud-Farlow, J. E., Chalk, A. M., Linder, S. E., Li, Q., Taylor, S., White, J. M., Pang, L., Liddicoat, B., Gupte, A., Li, J. B., et al. (2017) · Genome biology · doi:10.1186/s13059-017-1301-4 · Cited by 123
“Adar (Adar1; MGI allele: Adar; MGI:5805648), Ifih1 (Ifih1), Adar (Adar1; MGI allele: Adar; MGI:3029862), Adar (Adar1; MGI allele: Adar; MGI:3828307), and Rosa26-CreER (Gt(ROSA)26Sor) mice were on a backcrossed C57BL/6 background as previously described [14, 18, 19, 62, 63].”
MethodDas, L., & Vinayak, M. (2015) · PLoS ONE · doi:10.1371/journal.pone.0124000 · Cited by 124
“Consequence of p53 restoration is correlated with induction of apoptosis in lymphomas [49].”
BackgroundSelective Targeting of Cancer Stem Cells
Körkaya, H., & Wicha, M. S. (2007) · BioDrugs · doi:10.2165/00063030-200721050-00002 · Cited by 126
“[134] Most recently, two different studies have demonstrated that in p53-deficient tumors the restoration of p53 In addition to inducing differentiation, a number of stem cell results in tumor regression or arrest of tumor growth.[135,136] self-renewal pathways have been targeted for treatment of various human tumors.”
BackgroundOrigin of the brush cell lineage in the mouse intestinal epithelium
Bjerknes, M., Khandanpour, C., Möröy, T., Fujiyama, T., Hoshino, M., Klisch, T. J., Ding, Q., Gan, L., Wang, J., Martı́n, M. G., et al. (2011) · Developmental Biology · doi:10.1016/j.ydbio.2011.12.009 · Cited by 128
“For the Atoh1 conditional knockout study, a female homozygous Atoh1fl/fl mouse (Shroyer et al., 2007; The Jackson Laboratory, 008681) was mated with a male homozygous Rosa26CreERT2 mouse (Ventura et al., 2007; The Jackson Laboratory, 008463).”
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
