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.
Integrity signals
Registry
Cites
Statistics
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?
Some tumor cells retain the ability to senesce in response to DNA-damaging chemotherapy or p53 reactivation; in mice, this response arrests tumor progression.
“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]
Tumors induced to senesce in mice gradually regress.
“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]
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.
“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]
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.
“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]
The outcome of endogenous p53 reactivation can be senescence and/or cell death depending on the tumour type.
“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]
p53 is able to activate different checkpoint programs in different tissues.
“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]
Reactivation of p53-dependent senescence promotes regression of established p53-deficient tumors, facilitated by SASP-assisted recruitment of natural killer cells and macrophages to the tumor bed.
“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]
Mouse models clearly demonstrate that inactivation of p53 promotes tumorigenesis, whereas restoration of p53 causes regression of established tumours.
“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]
Tumour cells that undergo P53-triggered senescence are rapidly cleared in vivo.
“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]
Cites
Hanahan, D., & Weinberg, R. A. (2000) · Cell · doi:10.1016/s0092-8674(00)81683-9 · Cited by 29,219 · see citing works
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 · see citing works
<i>EGFR</i> 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 · see citing works
Generalized lacZ expression with the ROSA26 Cre reporter strain
Soriano, P. (1999) · Nature Genetics · doi:10.1038/5007 · Cited by 5,237 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
Self-citationAddiction to Oncogenes--the Achilles Heal of Cancer
Weinstein, I. (2002) · Science · doi:10.1126/science.1073096 · Cited by 1,753 · see citing works
Senescence in premalignant tumours
Collado, M., Gil, J., Efeyan, A., Guerra, C., Schuhmacher, A. J., Barradas, M., Benguría, A., Zaballos, A., Flores, J. M., Barbacid, M., et al. (2005) · Nature · doi:10.1038/436642a · Cited by 1,482 · see citing works
Mutant p53 gain of function in two mouse models of Li-Fraumeni syndrome
Olive, K. P., Tuveson, D. A., Ruhe, Z. C., Yin, B., Willis, N. A., Bronson, R. T., Crowley, D., & Jacks, T. (2004) · Cell · doi:10.1016/j.cell.2004.11.004 · Cited by 1,308 · see citing works
The IARC TP53 database: new online mutation analysis and recommendations to users
Olivier, M., Eeles, R., Hollstein, M., Khan, M. A., Harris, C. C., & Hainaut, P. (2002) · Human Mutation · doi:10.1002/humu.10081 · Cited by 1,248 · see citing works
Restoration of the tumor suppressor function to mutant p53 by a low-molecular-weight compound
Bykov, V. J. N., Issaeva, N., Shilov, A., Hultcrantz, M., Pugacheva, E., Chumakov, P., Bergman, J., Wiman, K. G., & Selivanova, G. (2002) · Nature Medicine · doi:10.1038/nm0302-282 · Cited by 1,067 · see citing works
Principles of Tumor Suppression
Sherr, C. J. (2004) · Cell · doi:10.1016/s0092-8674(03)01075-4 · Cited by 1,028 · see citing works
Essential role for oncogenic Ras in tumour maintenance
Chin, L., Tam, A., Pomerantz, J. H., Wong, M., Holash, J., Bardeesy, N., Shen, Q., O'Hagan, R., Pantginis, J., Zhou, H., et al. (1999) · Nature · doi:10.1038/22788 · Cited by 928 · see citing works
Branda, C., & Dymecki, S. M. (2004) · Developmental Cell · doi:10.1016/s1534-5807(03)00399-x · Cited by 863 · see citing works
Indra, A. K., Warot, X. M., Brocard, J., Bornert, J., Xiao, J. H., Chambon, P., & METZGER, D. (1999) · Nucleic Acids Research · doi:10.1093/nar/27.22.4324 · Cited by 758 · see citing works
Tumor suppression by Ink4a-Arf: progress and puzzles.
Lowe, S. W., & Sherr, C. J. (2003) · Current Opinion in Genetics & Development · doi:10.1016/s0959-437x(02)00013-8 · Cited by 699 · see citing works
Sustained Loss of a Neoplastic Phenotype by Brief Inactivation of MYC
Jain, M., Arvanitis, C., Chu, K., Dewey, W. C., Leonhardt, E. A., Trinh, M., Sundberg, C. D., Bishop, J. M., & Felsher, D. W. (2002) · Science · doi:10.1126/science.1071489 · Cited by 647 · see citing works
Pelengaris, S., Khan, M., & Evan, G. I. (2002) · Cell · doi:10.1016/s0092-8674(02)00738-9 · Cited by 623 · see citing works
Fisher, G. H., Wellen, S. L., Klimstra, D., Lenczowski, J. M., Tichelaar, J. W., Lizak, M. J., Whitsett, J. A., Koretsky, A., & Varmus, H. E. (2001) · Genes & Development · doi:10.1101/gad.947701 · Cited by 582 · see citing works
Probing tumor phenotypes using stable and regulated synthetic microRNA precursors
Dickins, R., Hemann, M., Zilfou, J. T., Simpson, D. R., Ibarra, I., Hannon, G., & Lowe, S. (2005) · Nature Genetics · doi:10.1038/ng1651 · Cited by 561 · see citing works
The pathological response to DNA damage does not contribute to p53-mediated tumour suppression
Christophorou, M. A., Ringshausen, I., Finch, A. J., Swigart, L. B., & Evan, G. I. (2006) · Nature · doi:10.1038/nature05077 · Cited by 382 · see citing works
p53-deficient mice are extremely susceptible to radiation-induced tumorigenesis
Kemp, C. J., Wheldon, T. E., & Balmain, A. (1994) · Nature Genetics · doi:10.1038/ng0994-66 · Cited by 366 · see citing works
Zhang, L., Yu, D., Hu, M., Xiong, S., Lang, A., Ellis, L. M., & Pollock, R. E. (2000) · PubMed · Cited by 230 · see citing works
Treatment of Terminal Peritoneal Carcinomatosis by a Transducible p53-Activating Peptide
Snyder, E. L., Meade, B. R., Saenz, C. C., & Dowdy, S. F. (2004) · PLoS Biology · doi:10.1371/journal.pbio.0020036 · Cited by 199 · see citing works
p53-Mediated Inhibition of Angiogenesis Through Up-Regulation of a Collagen Prolyl Hydroxylase
Teodoro, J. G., Parker, A. E., Zhu, X., & Green, M. R. (2006) · Science · doi:10.1126/science.1126391 · Cited by 195 · see citing works
Temporal dissection of p53 function in vitro and in vivo
Christophorou, M. A., Martı́n-Zanca, D., Soucek, L., Lawlor, E. R., Swigart, L. B., Verschuren, E. W., & Evan, G. I. (2005) · Nature Genetics · doi:10.1038/ng1572 · Cited by 182 · see citing works
Manipulation of the tumor suppressor p53 for potentiating cancer therapy
Haupt, S. M., & Haupt, Y. (2004) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2004.04.003 · Cited by 38 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
The senescence-associated secretory phenotype: the dark side of tumor suppression
Coppé, J.-P., Desprez, P.-Y., Krtolica, A., & Campisi, J. (2010) · Annual Review of Pathology: Mechanisms of Disease · doi:10.1146/annurev-pathol-121808-102144 · Cited by 5,206 · see citing works
Cellular senescence: when bad things happen to good cells
Campisi, J., & d'Adda di Fagagna, F. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2233 · Cited by 4,441 · see citing works
Coppé, J.-P., Patil, C. K., Rodier, F., Sun, Y., Muñoz, D. P., Goldstein, J., Nelson, P. S., Desprez, P.-Y., & Campisi, J. (2008) · PLoS Biology · doi:10.1371/journal.pbio.0060301 · Cited by 302 · see citing works
“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].”
BackgroundBlinded by the Light: The Growing Complexity of p53
Vousden, K. H., & Prives, C. (2009) · Cell · doi:10.1016/j.cell.2009.04.037 · Cited by 3,163 · see citing works
Cellular senescence: from physiology to pathology
Muñoz-Espín, D., & Serrano, M. (2014) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3823 · Cited by 2,818 · see citing works
p21 in cancer: Intricate networks and multiple activities
Abbas, T., & Dutta, A. (2009) · Nature Reviews Cancer · doi:10.1038/nrc2657 · Cited by 2,712 · see citing works
Senescence 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 · see citing works
Imaging in the era of molecular oncology
Weissleder, R., & Pittet, M. J. (2008) · Nature · doi:10.1038/nature06917 · Cited by 2,372 · see citing works
Self-citationA Large Intergenic Noncoding RNA Induced by p53 Mediates Global Gene Repression in the p53 Response
Huarte, M., Guttman, M., Feldser, D., Garber, M., Koziol, M. J., Kenzelmann-Broz, D., Khalil, A. M., Zuk, O., Amit, I., Rabani, M., et al. (2010) · Cell · doi:10.1016/j.cell.2010.06.040 · Cited by 2,053 · see citing works
Self-citationThe essence of senescence: Figure 1.
Kuilman, T., Michaloglou, C., Mooi, W. J., & Peeper, D. S. (2010) · Genes & Development · doi:10.1101/gad.1971610 · Cited by 2,038 · see citing works
Four faces of cellular senescence
Rodier, F., & Campisi, J. (2011) · Journal of Cell Biology · doi:10.1083/jcb.201009094 · Cited by 2,016 · see citing works
The first 30 years of p53: growing ever more complex.
Levine, A. J., & Oren, M. (2009) · Nature Reviews Cancer · doi:10.1038/nrc2723 · Cited by 1,967 · see citing works
Kastenhuber, E. R., & Lowe, S. W. (2017) · Cell · doi:10.1016/j.cell.2017.08.028 · Cited by 1,906 · see citing works
Ageing as a Risk Factor for Disease
Niccoli, T., & Partridge, L. (2012) · Current Biology · doi:10.1016/j.cub.2012.07.024 · Cited by 1,831 · see citing works
Principles of cancer therapy: oncogene and non-oncogene addiction
Luo, J., Solimini, N. L., & Elledge, S. J. (2009) · Cell · doi:10.1016/j.cell.2009.02.024 · Cited by 1,765 · see citing works
Cellular senescence in cancer and aging.
Collado, M., Blasco, M. A., & Serrano, M. (2007) · Cell · doi:10.1016/j.cell.2007.07.003 · Cited by 1,708 · see citing works
Ventura, A., Young, A. G., Winslow, M. M., Lintault, L., Meissner, A., Erkeland, S. J., Newman, J. J., Bronson, R. T., Crowley, D. G., Stone, J. R., et al. (2008) · Cell · doi:10.1016/j.cell.2008.02.019 · Cited by 1,592 · see citing works
Self-citationHow does p53 induce apoptosis and how does this relate to p53-mediated tumour suppression
Aubrey, B. J., Kelly, G. L., Janic, A., Herold, M. J., & Strasser, A. (2018) · Cell Death & Differentiation · doi:10.1038/cdd.2017.169 · Cited by 1,395 · see citing works
Unravelling mechanisms of p53-mediated tumour suppression
Bieging-Rolett, K. T., Mello, S. S., & Attardi, L. D. (2014) · Nature reviews. Cancer · doi:10.1038/nrc3711 · Cited by 1,389 · see citing works
Anselmo, A. C., & Mitragotri, S. (2016) · Bioengineering & Translational Medicine · doi:10.1002/btm2.10003 · Cited by 1,321 · see citing works
MDM2, MDMX and p53 in oncogenesis and cancer therapy
Wade, M., Li, Y.-C., & Wahl, G. M. (2013) · Nature Reviews Cancer · doi:10.1038/nrc3430 · Cited by 1,279 · see citing works
The Cell–Cycle Arrest and Apoptotic Functions of p53 in Tumor Initiation and Progression
Chen, J. (2016) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a026104 · Cited by 1,222 · see citing works
Imaging and drug delivery using theranostic nanoparticles
Janib, S. M., Moses, A. S., & MacKay, J. A. (2010) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2010.08.004 · Cited by 1,249 · see citing works
Living on a break: cellular senescence as a DNA-damage response
d'Adda di Fagagna, F. (2008) · Nature Reviews Cancer · doi:10.1038/nrc2440 · Cited by 1,170 · see citing works
Senescence in tumours: evidence from mice and humans
Collado, M., & Serrano, M. (2010) · Nature Reviews Cancer · doi:10.1038/nrc2772 · Cited by 1,124 · see citing works
Rodell, C. B., Arlauckas, S. P., Cuccarese, M. F., Garris, C. S., Li, R., Ahmed, M. S., Kohler, R. H., Pittet, M. J., & Weissleder, R. (2018) · Nature Biomedical Engineering · doi:10.1038/s41551-018-0236-8 · Cited by 1,099 · see citing works
Self-citationP53 in survival, death and metabolic health: a lifeguard with a licence to kill.
Kruiswijk, F., Labuschagne, C. F., & Vousden, K. H. (2015) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm4007 · Cited by 1,080 · see citing works
Alveolar progenitor and stem cells in lung development, renewal and cancer
Desai, T., Brownfield, D., & Krasnow, M. A. (2014) · Nature · doi:10.1038/nature12930 · Cited by 1,066 · see citing works
RIP3 mediates the embryonic lethality of caspase-8-deficient mice
Kaiser, W. J., Upton, J. W., Long, A. B., Livingston-Rosanoff, D., Daley-Bauer, L. P., Hakem, R., Caspary, T., & Mocarski, E. S. (2011) · Nature · doi:10.1038/nature09857 · Cited by 1,057 · see citing works
Feedback between p21 and reactive oxygen production is necessary for cell senescence
Passos, J. F., Nelson, G., Wang, C., Richter, T., Simillion, C., Proctor, C. J., Miwa, S., Olijslagers, S., Hallinan, J., Wipat, A., et al. (2010) · Molecular Systems Biology · doi:10.1038/msb.2010.5 · Cited by 1,019 · see citing works
“Although senescent cells can be cleared away efficiently from tissues under some conditions (Ventura et al, 2007; Krizhanovsky et al, 2008), cells bearing various senescence markers including DNA damage foci do accumulate in human (Dimri et al, 1995), primate (Herbig et al, 2006) and mouse (Wang et…”
The common biology of cancer and ageing
Finkel, T., Serrano, M., & Blasco, M. A. (2007) · Nature · doi:10.1038/nature05985 · Cited by 988 · see citing works
RNA editing by ADAR1 prevents MDA5 sensing of endogenous dsRNA as nonself
Liddicoat, B., Piskol, R., Chalk, A. M., Ramaswami, G., Higuchi, M., Hartner, J. C., Li, J. B., Seeburg, P. H., & Walkley, C. R. (2015) · Science · doi:10.1126/science.aac7049 · Cited by 955 · see citing works
Combination cancer immunotherapies tailored to the tumour microenvironment
Smyth, M. J., Ngiow, S. F., Ribas, A., & Teng, M. W. L. (2016) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2015.209 · Cited by 944 · see citing works
Targeting mutant p53 for efficient cancer therapy
Bykov, V. J. N., Eriksson, S. E., Bianchi, J., & Wiman, K. G. (2018) · Nature Reviews Cancer · doi:10.1038/nrc.2017.109 · Cited by 889 · see citing works
Awakening guardian angels: drugging the p53 pathway
Brown, C. J., Lain, S., Verma, C. S., Fersht, A. R., & Lane, D. P. (2009) · Nature Reviews Cancer · doi:10.1038/nrc2763 · Cited by 881 · see citing works
Exploiting senescence for the treatment of cancer
Wang, L., Lankhorst, L., & Bernards, R. (2022) · Nature Reviews Cancer · doi:10.1038/s41568-022-00450-9 · Cited by 867 · see citing works
The senescence-associated secretory phenotype and its physiological and pathological implications
Wang, B., Han, J., Elisseeff, J. H., & Demaria, M. (2024) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-024-00727-x · Cited by 948 · see citing works
Immortalization eliminates a roadblock during cellular reprogramming into iPS cells
Utikal, J. S., Polo, J. M., Stadtfeld, M., Maherali, N., Kulalert, W., Walsh, R. M., Khalil, A., Rheinwald, J. G., & Hochedlinger, K. (2009) · Nature · doi:10.1038/nature08285 · Cited by 828 · see citing works
Senescence and aging: the critical roles of p53
Rufini, A., Tucci, P., Celardo, I., & Melino, G. (2013) · Oncogene · doi:10.1038/onc.2012.640 · Cited by 798 · see citing works
Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition
Force, T. L., Krause, D. S., & Etten, R. A. V. (2007) · Nature reviews. Cancer · doi:10.1038/nrc2106 · Cited by 800 · see citing works
PTEN loss in the continuum of common cancers, rare syndromes and mouse models
Hollander, M. C., Blumenthal, G. M., & Dennis, P. A. (2011) · Nature reviews. Cancer · doi:10.1038/nrc3037 · Cited by 793 · see citing works
Senescence and cancer — role and therapeutic opportunities
Schmitt, C. A., Wang, B., & Demaria, M. (2022) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-022-00668-4 · Cited by 794 · see citing works
Ca2+ signalling checkpoints in cancer: remodelling Ca2+ for cancer cell proliferation and survival
Roderick, H. L., & Cook, S. J. (2008) · Nature reviews. Cancer · doi:10.1038/nrc2374 · Cited by 731 · see citing works
Drugging p53 in cancer: one protein, many targets
Hassin, O., & Oren, M. (2022) · Nature Reviews Drug Discovery · doi:10.1038/s41573-022-00571-8 · Cited by 736 · see citing works
Drugging the p53 pathway: understanding the route to clinical efficacy
Khoo, K. H., Verma, C. S., & Lane, D. P. (2014) · Nature Reviews Drug Discovery · doi:10.1038/nrd4236 · Cited by 723 · see citing works
Maximizing mouse cancer models
Frese, K. K., & Tuveson, D. A. (2007) · Nature reviews. Cancer · doi:10.1038/nrc2192 · Cited by 711 · see citing works
Self-citationTelomerase modulates Wnt signalling by association with target gene chromatin
Park, J.-I., Venteicher, A. S., Hong, J. Y., Choi, J., Jun, S., Shkreli, M., Chang, W., Meng, Z., Cheung, P., Ji, H., et al. (2009) · Nature · doi:10.1038/nature08137 · Cited by 707 · see citing works
Self-citationThe Tumor Suppressor p53 Regulates Polarity of Self-Renewing Divisions in Mammary Stem Cells
Cicalese, A., Bonizzi, G., Pasi, C. E., Faretta, M., Ronzoni, S., Giulini, B., Brisken, C., Minucci, S., Fiore, P. P. D., & Pelicci, P. G. (2009) · Cell · doi:10.1016/j.cell.2009.06.048 · Cited by 695 · see citing works
Structural Biology of the Tumor Suppressor p53
Joerger, A. C., & Fersht, A. R. (2008) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.77.060806.091238 · Cited by 699 · see citing works
The genetics of the p53 pathway, apoptosis and cancer therapy
Vázquez, A., Bond, E. E., Levine, A. J., & Bond, G. L. (2008) · Nature Reviews Drug Discovery · doi:10.1038/nrd2656 · Cited by 674 · see citing works
Shangary, S., Qin, D., McEachern, D., Liu, M., Miller, R. S., Qiu, S., Nikolovska-Coleska, Z., Ding, K., Wang, G., Chen, J., et al. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0708917105 · Cited by 660 · see citing works
Role of p53 in the Regulation of Cellular Senescence
Mijit, M., Caracciolo, V., Melillo, A., Amicarelli, F., & Giordano, A. (2020) · Biomolecules · doi:10.3390/biom10030420 · Cited by 639 · see citing works
Senescent cells as a source of inflammatory factors for tumor progression
Davalos, A. R., Coppe, J.-P., Campisi, J., & Desprez, P.-Y. (2010) · Cancer and Metastasis Reviews · doi:10.1007/s10555-010-9220-9 · Cited by 636 · see citing works
Shangary, S., & Wang, S. (2009) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.48.113006.094723 · Cited by 623 · see citing works
The effects of deregulated DNA damage signalling on cancer chemotherapy response and resistance
Bouwman, P., & Jonkers, J. (2012) · Nature Reviews Cancer · doi:10.1038/nrc3342 · Cited by 615 · see citing works
Vaseva, A. V., & Moll, U. M. (2008) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2008.10.005 · Cited by 618 · see citing works
Tumour suppression by p53: a role for the DNA damage response?
Meek, D. W. (2009) · Nature reviews. Cancer · doi:10.1038/nrc2716 · Cited by 604 · see citing works
miR-29 miRNAs activate p53 by targeting p85α and CDC42
Park, S. Y., Lee, J. H., Ha, M., Nam, J., & Kim, V. N. (2008) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.1533 · Cited by 608 · see citing works
PRIMA-1 reactivates mutant p53 by covalent binding to the core domain
Lambert, J. M. R., Gorzov, P., Veprintsev, D. B., Söderqvist, M., Segerbäck, D., Bergman, J., Fersht, A. R., Hainaut, P., Wiman, K. G., & Bykov, V. J. N. (2009) · Cancer Cell · doi:10.1016/j.ccr.2009.03.003 · Cited by 592 · see citing works
Cancer-Cell-Intrinsic Mechanisms Shaping the Tumor Immune Landscape
Wellenstein, M. D., & de Visser, K. E. (2018) · Immunity · doi:10.1016/j.immuni.2018.03.004 · Cited by 581 · see citing works
MAIT cells are imprinted by the microbiota in early life and promote tissue repair
Constantinides, M. G., Link, V. M., Tamoutounour, S., Wong, A. C., Perez-Chaparro, P. J., Han, S.-J., Chen, Y. E., Li, K., Farhat, S., Weckel, A., et al. (2019) · Science · doi:10.1126/science.aax6624 · Cited by 567 · see citing works
Removal of Shelterin Reveals the Telomere End-Protection Problem
Sfeir, A. J., & de Lange, T. (2012) · Science · doi:10.1126/science.1218498 · Cited by 578 · see citing works
Tumor Suppressive Functions of p53Preprint
Zilfou, J. T., & Lowe, S. W. (2009) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a001883 · Cited by 572 · see citing works
Meta-hallmarks of aging and cancer
López-Otín, C., Pietrocola, F., Roiz-Valle, D., Galluzzi, L., & Kroemer, G. (2023) · Cell Metabolism · doi:10.1016/j.cmet.2022.11.001 · Cited by 529 · see citing works
Distinct p53 Transcriptional Programs Dictate Acute DNA-Damage Responses and Tumor Suppression
Brady, C. A., Jiang, D., Mello, S. S., Johnson, T. M., Jarvis, L. A., Kozak, M. M., Broz, D. K., Basak, S., Park, E. J., McLaughlin, M. E., et al. (2011) · Cell · doi:10.1016/j.cell.2011.03.035 · Cited by 533 · see citing works
Self-citationRodier, F., Muñoz, D. P., Teachenor, R., Chu, V., Le, O., Bhaumik, D., Coppé, J.-P., Campeau, E., Beauséjour, C. M., Kim, S.-H., et al. (2011) · Journal of Cell Science · doi:10.1242/jcs.071340 · Cited by 535 · see citing works
Coppé, J.-P., Rodier, F., Patil, C. K., Freund, A., Desprez, P.-Y., & Campisi, J. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.257071 · Cited by 506 · see citing works
Requirement for NF-κB signalling in a mouse model of lung adenocarcinoma
Meylan, E., Dooley, A. L., Feldser, D. M., Shen, L., Turk, E., Ouyang, C., & Jacks, T. (2009) · Nature · doi:10.1038/nature08462 · Cited by 514 · see citing works
Self-citationSenescent Cells in Cancer Therapy: Friends or Foes?
Wang, B., Kohli, J., & Demaria, M. (2020) · Trends in Cancer · doi:10.1016/j.trecan.2020.05.004 · Cited by 508 · see citing works
Genetically engineered mouse models in oncology research and cancer medicine
Kersten, K., de Visser, K. E., van Miltenburg, M. H., & Jonkers, J. (2017) · EMBO Molecular Medicine · doi:10.15252/emmm.201606857 · Cited by 502 · see citing works
Reciprocal regulation of p53 and malic enzymes modulates metabolism and senescence
Jiang, P., Du, W., Mancuso, A., Wellen, K. E., & Yang, X. (2013) · Nature · doi:10.1038/nature11776 · Cited by 491 · see citing works
The Cytokine GM-CSF Drives the Inflammatory Signature of CCR2+ Monocytes and Licenses Autoimmunity
Croxford, A. L., Lanzinger, M., Hartmann, F. J., Schreiner, B., Mair, F., Pelczar, P., Clausen, B. E., Jung, S., Greter, M., & Becher, B. (2015) · Immunity · doi:10.1016/j.immuni.2015.08.010 · Cited by 484 · see citing works
Development and plasticity of meningeal lymphatic vessels
Antila, S., Karaman, S., Nurmi, H. J., Airavaara, M., Voutilainen, M. H., Mathivet, T., Chilov, D., Li, Z., Koppinen, T. K., Park, J., et al. (2017) · The Journal of Experimental Medicine · doi:10.1084/jem.20170391 · Cited by 469 · see citing works
Tumours with PI3K activation are resistant to dietary restriction
Kalaany, N. Y., & Sabatini, D. M. (2009) · Nature · doi:10.1038/nature07782 · Cited by 468 · see citing works
The p53 network: cellular and systemic DNA damage responses in aging and Cancer
Reinhardt, H. C., & Schumacher, B. (2012) · Trends in Genetics · doi:10.1016/j.tig.2011.12.002 · Cited by 458 · see citing works
Inside and out: the activities of senescence in cancer
Pérez-Mancera, P. A., Young, A. R. J., & Narita, M. (2014) · Nature Reviews Cancer · doi:10.1038/nrc3773 · Cited by 462 · see citing works
Matés, J. M., Segura, J. A., Alonso, F. J., & Márquez, J. (2008) · Archives of Toxicology · doi:10.1007/s00204-008-0304-z · Cited by 460 · see citing works
Dimitrova, N., Zamudio, J. R., Jong, R. M., Soukup, D., Resnick, R., Sarma, K., Ward, A. J., Raj, A., Lee, J. T., Sharp, P. A., et al. (2014) · Molecular Cell · doi:10.1016/j.molcel.2014.04.025 · Cited by 445 · see citing works
Self-citationGodár, S., Ince, T. A., Bell, G. W., Feldser, D. M., Donaher, J. L., Bergh, J. C. S., Liu, A. Y., Miu, K., Watnick, R. S., Reinhardt, F., et al. (2008) · Cell · doi:10.1016/j.cell.2008.06.006 · Cited by 455 · see citing works
Self-citationPichiorri, F., Suh, S.-S., Rocci, A., De Luca, L., Taccioli, C., Santhanam, R., Zhou, W., Benson, D. M., Hofmainster, C., Alder, H., et al. (2010) · Cancer Cell · doi:10.1016/j.ccr.2010.09.005 · Cited by 436 · see citing works
RetractedGenetic dissection of the miR-17∼92 cluster of microRNAs in Myc-induced B-cell lymphomasPreprint
Mu, P., Han, Y.-C., Betel, D., Yao, E. S., Squatrito, M., Ogrodowski, P., de Stanchina, E., D’Andrea, A., Sander, C., & Ventura, A. (2009) · Genes & Development · doi:10.1101/gad.1872909 · Cited by 449 · see citing works
Self-citationOncogene addiction: setting the stage for molecularly targeted cancer therapyPreprint
Sharma, S. V., & Settleman, J. E. (2007) · Genes & Development · doi:10.1101/gad.1609907 · Cited by 442 · see citing works
Dicer1 functions as a haploinsufficient tumor suppressorPreprint
Kumar, M. S., Pester, R. E., Chen, C. Y., Lane, K. M., Chin, C., Lü, J., Kirsch, D. G., Golub, T. R., & Jacks, T. (2009) · Genes & Development · doi:10.1101/gad.1848209 · Cited by 437 · see citing works
Self-citationPro-senescence therapy for cancer treatment
Nardella, C., Clohessy, J. G., Alimonti, A., & Pandolfi, P. P. (2011) · Nature Reviews Cancer · doi:10.1038/nrc3057 · Cited by 437 · see citing works
Iannello, A., Thompson, T. W., Ardolino, M., Lowe, S. W., & Raulet, D. H. (2013) · Journal of Experimental Medicine · doi:10.1084/jem.20130783 · Cited by 414 · see citing works
Polylox barcoding reveals haematopoietic stem cell fates realized in vivo
Pei, W., Feyerabend, T. B., Rößler, J., Wang, X., Postrach, D., Busch, K., Rode, I., Klapproth, K., Dietlein, N., Quedenau, C., et al. (2017) · Nature · doi:10.1038/nature23653 · Cited by 412 · see citing works
Telomere dysfunction and tumour suppression: the senescence connection
Deng, Y., Chan, S. S., & Chang, S. (2008) · Nature Reviews Cancer · doi:10.1038/nrc2393 · Cited by 411 · see citing works
Skp2 targeting suppresses tumorigenesis by Arf-p53-independent cellular senescence
Lin, H.-K., Chen, Z., Wang, G., Nardella, C., Lee, S.-W., Chan, C.-H., Yang, W.-L., Wang, J., Egia, A., Nakayama, K. I., et al. (2010) · Nature · doi:10.1038/nature08815 · Cited by 400 · see citing works
Cellular senescence is an important mechanism of tumor regression upon c-Myc inactivation
Wu, C.-H., van Riggelen, J., Yetil, A., Fan, A. C., Bachireddy, P., & Felsher, D. W. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0701953104 · Cited by 405 · see citing works
Oncogenic stress sensed by the immune system: role of natural killer cell receptors
Raulet, D. H., & Guerra, N. (2009) · Nature reviews. Immunology · doi:10.1038/nri2604 · Cited by 396 · see citing works
Mitochondria-mediated apoptosis in mammals
Xiong, S., Mu, T., Wang, G., & Jiang, X. (2014) · Protein & Cell · doi:10.1007/s13238-014-0089-1 · Cited by 400 · see citing works
Many roads lead to oncogene-induced senescence
Courtois-Cox, S., Jones, S. L., & Cichowski, K. (2008) · Oncogene · doi:10.1038/sj.onc.1210950 · Cited by 397 · see citing works
Structural basis for high-affinity peptide inhibition of p53 interactions with MDM2 and MDMX
Pazgier, M., Liu, M., Zou, G., Yuan, W., Li, C., Li, C., Li, J., Monbo, J., Zella, D., Tarasov, S. G., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0900947106 · Cited by 391 · see citing works
The Lkb1 metabolic sensor maintains haematopoietic stem cell survival
Gurumurthy, S., Xie, S. Z.-J., Alagesan, B., Kim, J., Yusuf, R. Z., Sáez, B., Tzatsos, A., Ozsolak, F., Milos, P. M., Ferrari, F., et al. (2010) · Nature · doi:10.1038/nature09572 · Cited by 391 · see citing works
Brady, C. A., & Attardi, L. D. (2010) · Journal of Cell Science · doi:10.1242/jcs.064501 · Cited by 374 · see citing works
Shaping Genetic Alterations in Human Cancer: The p53 Mutation Paradigm
Soussi, T., & Wiman, K. G. (2007) · Cancer Cell · doi:10.1016/j.ccr.2007.10.001 · Cited by 366 · see citing works
Mutant p53 as a target for cancer treatment
Duffy, M. J., Synnott, N. C., & Crown, J. P. (2017) · European Journal of Cancer · doi:10.1016/j.ejca.2017.06.023 · Cited by 361 · see citing works
Curcumin as an Alternative Epigenetic Modulator: Mechanism of Action and Potential Effects
Hassan, F., Rehman, M. S.-U., Khan, M. S., Ali, M. A., Javed, A., Nawaz, A. S., & Yang, C. (2019) · Frontiers in Genetics · doi:10.3389/fgene.2019.00514 · Cited by 369 · see citing works
Mdm2-mediated ubiquitylation: p53 and beyond
Marine, J.-C., & Lozano, G. (2010) · Cell Death & Differentiation · doi:10.1038/cdd.2009.68 · Cited by 354 · see citing works
The Tumor Suppressor p53: From Structures to Drug DiscoveryPreprint
Joerger, A. C., & Fersht, A. R. (2010) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a000919 · Cited by 356 · see citing works
- 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
- Health Sciences › Medicine › Physiology › 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
