The DOI matches its Crossref record; 95 of the 96 references it cites were found in a registry or an index; 1 of the 121 sources its claims cite were checked for support.
p53 at a glance
Open accessAbstract
Since its discovery in 1979, the role of the p53 protein in cancer has been studied intensively (Levine and Oren, 2009). p53 is a crucial tumor suppressor, long-recognized to suppress cancer through the induction of cell-cycle-arrest or apoptosis programs in response to a plethora of different cellular stress signals. Although this model paints a seemingly simple picture, the longer that p53 is studied, the more it confronts researchers with new questions about its functions and mechanisms of action. The tumor-suppressor function of p53 extends beyond the capacity to trigger cell-cycle arrest and apoptosis, and novel activities that impact tumor suppression are perpetually emerging, including the regulation of metabolism, autophagy and the oxidative status of the cell. Moreover, because it acts as a crucial node downstream of diverse stress signals, it is perhaps not surprising that p53 has been recently discovered to have broader roles in physiology and pathology. In this article and its accompanying poster, we outline the basic molecular and cellular functions of p53, describe the intricate network of p53 mediators, and provide insight into the roles of p53 in normal physiology and human disease.Analysis of human cancers reveals a fundamental role for p53 in tumor suppression. More than half of human cancers, of a wide variety of types, harbor p53 (TP53) mutations, and inheritance of a mutant p53 allele predisposes humans to the Li-Fraumeni cancer syndrome (Olivier et al., 2010). Unequivocal confirmation of the crucial role for p53 in tumor suppression was demonstrated by the completely penetrant cancer phenotype of p53-null mice (Kenzelmann Broz and Attardi, 2010). p53 restricts tumor development by serving as a sensor of cellular stress, responding to diverse signals, including DNA damage, hypoxia, oncogene expression, nutrient deprivation and ribosome dysfunction, and limiting the propagation of cells under these adverse conditions (Vousden and Prives, 2009). In metazoans, an ancestral function of p53 is thought to be its ability to trigger programmed cell death (also known as apoptosis) in response to DNA damage, as a measure to preserve the integrity of the germ line (Junttila and Evan, 2009; Lu and Abrams, 2006; Lu et al., 2009). Subsequently, with the evolution of longer-living organisms, p53 is thought to have acquired the ability to respond to oncogenic signals, promoting apoptosis or senescence – a permanent cell-cycle-arrest response – as a safeguard against neoplasia. Thus, in cells exposed to potent stress signals, p53 drives irreversible programs of apoptosis or senescence to cull irreparably damaged or malignant cells, for the ultimate benefit of the organism (Vousden and Prives, 2009). Alternatively, under conditions of low-level stress, p53 elicits protective, pro-survival responses, such as temporary cell-cycle arrest, DNA repair and antioxidant protein production, to maintain genome integrity and viability in cells that sustain limited, reparable damage. These various responses rely on the ability of p53 to function as a transcriptional activator of a panoply of target genes, although transactivation-independent activities ascribed to p53 can also contribute to p53-mediated responses, as highlighted below.Similarly to other transcription factors, p53 has a modular protein domain structure (Joerger and Fersht, 2007; Vousden and Prives, 2009). The N-terminus of p53 comprises two transcriptional activation domains (TADs), TAD1 and TAD2, which span amino acid residues 1-40 and 40-60, respectively. These domains can independently enhance transcription of p53 target genes by recruiting histone-modifying enzymes, components of the basal transcriptional machinery and coactivator complexes, such as STAGA and Mediator (Gamper and Roeder, 2008; Joerger and Fersht, 2007). C-terminal to the transactivation domains, between residues 60-95, lies the proline-rich domain (PRD), which was originally proposed to participate in protein-protein interactions on the basis of the presence of PxxP motifs that resemble Src homology 3 (SH3)-domain-binding regions (Toledo et al., 2006; Toledo et al., 2007). However, a structural function might be the main role of this domain because knock-in mice carrying proline-to-alanine point mutations in the putative protein-protein interaction sites of this domain appear normal, whereas complete domain deletion disrupts p53 tumor-suppressor function. The central core of p53, which spans residues 100-300, comprises the DNA-binding domain that is responsible for sequence-specific binding of the protein to p53 response elements in DNA. Most cancer-associated p53 mutations are missense mutations in this domain and incapacitate DNA binding, illuminating the key importance of DNA binding for p53-mediated tumor suppression. Tumor-derived p53 mutations either alter residues that are essential for direct contact with p53 response elements (contact mutants) or impair proper folding of
Overview
CoChat Summary
TL;DR
This review summarizes p53 as a central stress-sensing tumor suppressor, covering its protein domains, transcriptional and cytoplasmic functions, regulation by MDM2/MDMX, and broader roles in physiology and disease. It emphasizes that p53 outcomes are highly context-dependent and that its biology is more complex than the canonical cell-cycle-arrest/apoptosis model.
Key findings
- p53 is mutated in more than half of human cancers of many types; inherited mutant p53 predisposes to Li-Fraumeni syndrome, and p53-null mice have a completely penetrant cancer phenotype.
- p53 has a modular domain structure: TAD1 (residues 1–40), TAD2 (40–60), proline-rich domain (60–95), DNA-binding core (100–300), tetramerization domain (325–356), and C-terminal basic domain (363–393). The six most common cancer hotspot residues are R175, G245, R248, R249, R273 and R282.
- p53 binds response elements as a tetramer, classically two half sites of RRRCWWGYYY separated by 0–13 bp. Severe stress drives apoptosis or senescence; low-level stress promotes temporary arrest, DNA repair and antioxidant responses. p53 also has cytoplasmic roles in apoptosis and autophagy, metabolic effects, and non-cell-autonomous tumor-suppressive effects.
- MDM2 and MDMX regulate p53 levels and activity. Mdm2-null mice show very early embryonic lethality that is completely rescued by p53 loss; Mdmx-null mice show p53-dependent embryonic lethality later in embryogenesis. p53 also activates MDM2 transcription, forming a negative-feedback loop.
Methods
- Narrative review article with an accompanying poster; no primary experimental design, sample or new data are reported.
- Synthesizes published literature on p53 molecular and cellular functions, its regulators, and its roles in normal physiology and human disease.
- No systematic review, meta-analysis or quantitative synthesis methods are stated.
Limitations
- The authors state that capturing the complete complexity of p53 function is beyond the scope of the article; they note omitted topics including post-translational modifications, p53 polymorphisms, p53 isoforms, and p63/p73 family interplay.
- The text highlights unresolved or controversial areas, including pro-aging versus anti-aging roles of p53 in different mouse models, the dual role of autophagy in tumor suppression, uncertainty about the full importance of the MDMX-MDM2 interaction, complexity of C-terminal lysine modifications, and unknown significance of p53 isoforms.
- Evident from the text: as a narrative review, it does not provide a systematic search strategy, quantitative synthesis, or primary data, and many conclusions rely on cited reviews and model systems.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
1 Valid · 0 Not valid · 68 Not checked · 34 Own results and interpretations
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“exciting recent findings have shown that reactivation of p53 expression in mouse models induces tumor regression (Martins et al., 2006; Ventura et al., 2007; Xue et al., 2007).”
What the sources say
- Not checked yetcites Martins et al., 2006 source
- Not checked yetcites Ventura et al., 2007 source
- Supportedcites Xue et al., 2007 source
Our copy of Xue et al. (2007) states directly that reactivating endogenous p53 in p53-deficient tumours produces complete tumour regression in vivo: the Abstract reports 'even brief reactivation of endogenous p53 in p53-deficient tumours can produce complete tumour regressions', and the results describe hepatocarcinomas involuting to near-undetectable levels within 12 days of Dox-mediated p53 restoration (p. 1, Fig. 1b) and regressing after only 4 days of Dox (p. 2, Fig. 1e), including in a subcutaneous setting and in tumours co-expressing activated Akt or oncogenic K-ras. The mechanism (senescence plus innate immune clearance) is additional detail not required by the citing sentence, which is offered as one of three mouse-model citations for p53 reactivation-induced regression. (LLM, conf=0.95)
boostedstates a cause- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A statement the paper makes itself — it cites no source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In response to sustained or severe stress signals, p53 drives irreversible apoptosis or senescence programs.”
plainstates a cause- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“Additionally, a major component of repression probably occurs through indirect mechanisms, such as by p53-dependent activation of microRNAs or lincRNAs that repress gene expression (Guttman et al., 2009; He et al., 2007; Menendez et al., 2009; Riley et al., 2008).”
What the sources say
hedgedstates a possible cause- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A statement the paper makes itself — it cites no source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“p53 also has a complex role in regulating autophagy.”
plainstates a cause- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A statement the paper makes itself — it cites no source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The central core of p53, which spans residues 100-300, comprises the DNA-binding domain that is responsible for sequence-specific binding of the protein to p53 response elements in DNA.”
plainstates a cause- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
58 more claims
Create a free account to see all 103 claims and to verify the 108 references still open.
- It may state two separate claims as one. 33
- Probably not a substantial claim. 9
Citations
Cites
Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals
Guttman, M., Amit, I., Garber, M., French, C., Lin, M. F., Feldser, D., Huarte, M., Zuk, O., Carey, B. W., Cassady, J. P., et al. (2009) · Nature · doi:10.1038/nature07672 · Cited by 4,098
Blinded 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
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
Vousden, K. H., & Lane, D. P. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2147 · Cited by 2,272
TP53 mutations in human cancers: origins, consequences, and clinical use.
Olivier, M., Hollstein, M., & Hainaut, P. (2010) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a001008 · Cited by 2,199 · cited 1×
“More than half of human cancers, of a wide variety of types, harbor p53 (TP53) mutations, and inheritance of a mutant p53 allele predisposes humans to the Li-Fraumeni cancer syndrome (Olivier et al., 2010).”
BackgroundSenescence of Activated Stellate Cells Limits Liver Fibrosis
Krizhanovsky, V., Yon, M., Dickins, R. A., Hearn, S., Simon, J., Miething, C., Yee, H., Zender, L., & Lowe, S. W. (2008) · Cell · doi:10.1016/j.cell.2008.09.015 · Cited by 2,027
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
Transcriptional control of human p53-regulated genes
Riley, T., Sontag, E., Chen, P., & Levine, A. (2008) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2395 · Cited by 1,921
Restoration of p53 function leads to tumour regression in vivo
Ventura, A., Kirsch, D. G., McLaughlin, M. E., Tuveson, D. A., Grimm, J., Lintault, L., Newman, J., Reczek, E. E., Weissleder, R., & Jacks, T. (2007) · Nature · doi:10.1038/nature05541 · Cited by 1,820 · cited 1×
“Indeed, exciting recent findings have shown that reactivation of p53 expression in mouse models induces tumor regression (Martins et al., 2006; Ventura et al., 2007; Xue et al., 2007).”
Backgroundp53 Has a Direct Apoptogenic Role at the Mitochondria
Mihara, M., Erster, S., Zaika, A., Petrenko, O., Chittenden, T., Pancoska, P., & Moll, U. M. (2003) · Molecular Cell · doi:10.1016/s1097-2765(03)00050-9 · Cited by 1,777
Kruse, J.-P., & Gu, W. (2009) · Cell · doi:10.1016/j.cell.2009.04.050 · Cited by 1,610 · cited 3×
“…diffusion that helps p53 hone in on its response elements, as well as undergoing extensive posttranslational modifications that modulate p53 stabilization and sequence-specific DNA binding (Kruse and Gu, 2009; Laptenko and Prives, 2006; Liu and Kulesz-Martin, 2006; Murray-Zmijewski et al., 2008).”
Backgroundp53 mutant mice that display early ageing-associated phenotypes
Tyner, S. D., Venkatachalam, S., Choi, J., Jones, S., Ghebranious, N., Igelmann, H., Lu, X., Soron, G., Cooper, B., Brayton, C., et al. (2002) · Nature · doi:10.1038/415045a · Cited by 1,459 · cited 1×
“Specifically, mice with extra copies of both the Arf and p53 genes exhibit increased longevity, whereas mice expressing p53 truncation mutants that lead to aberrant p53 activation display reduced longevity and signs of premature aging (Maier et al., 2004; Matheu et al., 2007; Tyner et al., 2002).”
BackgroundRescue of early embryonic lethality in mdm2-deficient mice by deletion of p53
de Oca Luna, R. M., Wagner, D. S., & Lozano, G. (1995) · Nature · doi:10.1038/378203a0 · Cited by 1,420 · cited 1×
“The crucial importance of MDM2 in regulating p53 was demonstrated using Mdm2-null mice, which display very early embryonic lethality (Jones et al., 1995; Montes de Oca Luna et al., 1995).”
BackgroundMutant 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
Rescue of embryonic lethality in Mdm2-deficient mice by absence of p53
Jones, S. N., Roe, A. E., Donehower, L. A., & Bradley, A. (1995) · Nature · doi:10.1038/378206a0 · Cited by 1,280 · cited 1×
“The crucial importance of MDM2 in regulating p53 was demonstrated using Mdm2-null mice, which display very early embryonic lethality (Jones et al., 1995; Montes de Oca Luna et al., 1995).”
BackgroundRegulation of autophagy by cytoplasmic p53
Tasdemir, E., Maiuri, M. C., Galluzzi, L., Vitale, I., Djavaheri-Mergny, M., D'Amelio, M., Criollo, A., Morselli, E., Zhu, C., Harper, F., et al. (2008) · Nature Cell Biology · doi:10.1038/ncb1730 · Cited by 1,132
When mutants gain new powers: News from the mutant p53 field
Brosh, R., & Rotter, V. (2009) · Nature Reviews Cancer · doi:10.1038/nrc2693 · Cited by 1,132
Modulation of microRNA processing by p53
Suzuki, H. I., Yamagata, K., Sugimoto, K., Iwamoto, T., Kato, S., & Miyazono, K. (2009) · Nature · doi:10.1038/nature08199 · Cited by 1,124
The antioxidant function of the p53 tumor suppressor
Sablina, A. A., Budanov, A. V., Ilyinskaya, G. V., Agapova, L. S., Kravchenko, J. E., & Chumakov, P. M. (2005) · Nature Medicine · doi:10.1038/nm1320 · Cited by 1,121
Cytoplasmic functions of the tumour suppressor p53
Green, D. R., & Kroemer, G. (2009) · Nature · doi:10.1038/nature07986 · Cited by 1,106
Gain of function of a p53 hot spot mutation in a mouse model of Li-Fraumeni syndrome
Lang, G. A., Iwakuma, T., Suh, Y.-A., Liu, G., Rao, V. A., Parant, J. M., Valentin-Vega, Y. A., Terzian, T., Caldwell, L. C., Strong, L. C., et al. (2004) · Cell · doi:10.1016/j.cell.2004.11.006 · Cited by 1,069
Vousden, K. H., & Ryan, K. M. (2009) · Nature Reviews Cancer · doi:10.1038/nrc2715 · Cited by 959
p53 ubiquitination: Mdm2 and beyond
Brooks, C. L., & Gu, W. (2006) · Molecular Cell · doi:10.1016/j.molcel.2006.01.020 · Cited by 924
A crucial role for adipose tissue p53 in the regulation of insulin resistance
Minamino, T., Orimo, M., Shimizu, I., Kunieda, T., Yokoyama, M., Ito, T., Nojima, A., Nabetani, A., Oike, Y., Matsubara, H., et al. (2009) · Nature Medicine · doi:10.1038/nm.2014 · Cited by 891
p53-Dependent apoptosis in the absence of transcriptional activation of p53-target genes
Caelles, C., Helmberg, A., & Karin, M. (1994) · Nature · doi:10.1038/370220a0 · Cited by 843
ROS and p53: A versatile partnership
Liu, B., Chen, Y., & St. Clair, D. K. (2008) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2008.01.011 · Cited by 830
Mutant p53 drives invasion by promoting integrin recycling
Muller, P. A. J., Caswell, P. T., Doyle, B., Iwanicki, M. P., Tan, E. H., Karim, S., Lukashchuk, N., Gillespie, D. A., Ludwig, R. L., Gosselin, P., et al. (2009) · Cell · doi:10.1016/j.cell.2009.11.026 · Cited by 796
Mitochondrial p53 activates Bak and causes disruption of a Bak–Mcl1 complex
Leu, J. I.-J., Dumont, P., Hafey, M., Murphy, M. E., & George, D. L. (2004) · Nature Cell Biology · doi:10.1038/ncb1123 · Cited by 770
The 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., Di Fiore, P. P., & Pelicci, P. G. (2009) · Cell · doi:10.1016/j.cell.2009.06.048 · Cited by 696
Central role of p53 in the suntan response and pathologic hyperpigmentation
Cui, R., Widlund, H. R., Feige, E., Lin, J. Y., Wilensky, D. L., Igras, V. E., D'Orazio, J., Fung, C. Y., Schanbacher, C. F., Granter, S. R., et al. (2007) · Cell · doi:10.1016/j.cell.2006.12.045 · Cited by 657
Kortlever, R. M., Higgins, P. J., & Bernards, R. (2006) · Nature Cell Biology · doi:10.1038/ncb1448 · Cited by 637 · cited 2×
“C 1 40 60 95 100 300 325 356 393 TAD1 TAD2 PRD DNA binding Tet p53 p53 Post-translational modifications of p53 and MDM2 DNA damage Nucleotide depletion Telomere attrition *Oncogene expression Oxidative stress Nutrient deprivation Hypoxia *Ribosomal dysfunction • Ubiquitylation • Binding and masking of TAD Binding Bind…”
BackgroundVaseva, A. V., & Moll, U. M. (2009) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2008.10.005 · Cited by 618
Modeling the Therapeutic Efficacy of p53 Restoration in Tumors
Martins, C. P., Brown-Swigart, L., & Evan, G. I. (2006) · Cell · doi:10.1016/j.cell.2006.12.007 · Cited by 600 · cited 1×
“Indeed, exciting recent findings have shown that reactivation of p53 expression in mouse models induces tumor regression (Martins et al., 2006; Ventura et al., 2007; Xue et al., 2007).”
BackgroundSignaling to p53: ribosomal proteins find their way
Zhang, Y., & Lu, H. (2009) · Cancer Cell · doi:10.1016/j.ccr.2009.09.024 · Cited by 591
Modulation of mammalian life span by the short isoform of p53
Maier, B., Gluba, W., Bernier, B., Turner, T., Mohammad, K., Guise, T., Sutherland, A., Thorner, M., & Scrable, H. (2004) · Genes & Development · doi:10.1101/gad.1162404 · Cited by 586
A subset of p53-deficient embryos exhibit exencephaly
Sah, V. P., Attardi, L. D., Mulligan, G. J., Williams, B. O., Bronson, R. T., & Jacks, T. (1995) · Nature Genetics · doi:10.1038/ng0695-175 · Cited by 580
Self-citationTumor Suppressive Functions of p53
Zilfou, J. T., & Lowe, S. W. (2009) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a001883 · Cited by 575
The role of p53 in determining sensitivity to radiotherapy
Gudkov, A. V., & Komarova, E. A. (2003) · Nature Reviews Cancer · doi:10.1038/nrc992 · Cited by 572
The expanding universe of p53 targets
Menendez, D., Inga, A., & Resnick, M. A. (2009) · Nature Reviews Cancer · doi:10.1038/nrc2730 · Cited by 568
p53 Regulates Hematopoietic Stem Cell Quiescence
Liu, Y., Elf, S. E., Miyata, Y., Sashida, G., Liu, Y., Huang, G., Di Giandomenico, S., Lee, J. M., Deblasio, A., Menendez, S., et al. (2009) · Cell Stem Cell · doi:10.1016/j.stem.2008.11.006 · Cited by 547
microRNAs join the p53 network — another piece in the tumour-suppression puzzle
He, L., He, X., Lowe, S. W., & Hannon, G. J. (2007) · Nature Reviews Cancer · doi:10.1038/nrc2232 · Cited by 547
PUMA Couples the Nuclear and Cytoplasmic Proapoptotic Function of p53
Chipuk, J. E., Bouchier-Hayes, L., Kuwana, T., Newmeyer, D. D., & Green, D. R. (2005) · Science · doi:10.1126/science.1114297 · Cited by 546
Yu, Y., Khan, J., Khanna, C., Helman, L., Meltzer, P. S., & Merlino, G. (2004) · Nature Medicine · doi:10.1038/nm966 · Cited by 525
Parant, J., Chavez-Reyes, A., Little, N. A., Yan, W., Reinke, V., Jochemsen, A. G., & Lozano, G. (2001) · Nature Genetics · doi:10.1038/ng714 · Cited by 517
Transcriptional regulation by p53: one protein, many possibilities
Laptenko, O., & Prives, C. (2006) · Cell Death & Differentiation · doi:10.1038/sj.cdd.4401916 · Cited by 505
p53 Mediates Cellular Dysfunction and Behavioral Abnormalities in Huntington’s Disease
Bae, B.-I., Xu, H., Igarashi, S., Fujimuro, M., Agrawal, N., Taya, Y., Hayward, S. D., Moran, T. H., Montell, C., Ross, C. A., et al. (2005) · Neuron · doi:10.1016/j.neuron.2005.06.005 · Cited by 485
High-frequency developmental abnormalities in p53-deficient mice
Armstrong, J. F., Kaufman, M. H., Harrison, D. J., & Clarke, A. R. (1995) · Current Biology · doi:10.1016/s0960-9822(95)00183-7 · Cited by 467
Delayed ageing through damage protection by the Arf/p53 pathway
Matheu, A., Maraver, A., Klatt, P., Flores, I., Garcia-Cao, I., Borras, C., Flores, J. M., Viña, J., Blasco, M. A., & Serrano, M. (2007) · Nature · doi:10.1038/nature05949 · Cited by 466
The p53 orchestra: Mdm2 and Mdmx set the tone
Wade, M., Wang, Y. V., & Wahl, G. M. (2010) · Trends in Cell Biology · doi:10.1016/j.tcb.2010.01.009 · Cited by 450
p53 regulates maternal reproduction through LIF
Hu, W., Feng, Z., Teresky, A. K., & Levine, A. J. (2007) · Nature · doi:10.1038/nature05993 · Cited by 445
Prevention of the neurocristopathy Treacher Collins syndrome through inhibition of p53 function
Jones, N. C., Lynn, M. L., Gaudenz, K., Sakai, D., Aoto, K., Rey, J.-P., Glynn, E. F., Ellington, L., Du, C., Dixon, J., et al. (2008) · Nature Medicine · doi:10.1038/nm1725 · Cited by 428
A complex barcode underlies the heterogeneous response of p53 to stress
Murray-Zmijewski, F., Slee, E. A., & Lu, X. (2008) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2451 · Cited by 420
p53 suppresses the self-renewal of adult neural stem cells
Meletis, K., Wirta, V., Hede, S.-M., Nistér, M., Lundeberg, J., & Frisén, J. (2006) · Development · doi:10.1242/dev.02208 · Cited by 413
Culmsee, C., & Mattson, M. P. (2005) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2005.03.149 · Cited by 389
Ribosomal mutations cause p53-mediated dark skin and pleiotropic effects
McGowan, K. A., Li, J. Z., Park, C. Y., Beaudry, V., Tabor, H. K., Sabnis, A. J., Zhang, W., Fuchs, H., de Angelis, M. H., Myers, R. M., et al. (2008) · Nature Genetics · doi:10.1038/ng.188 · Cited by 364
Self-citationKeeping p53 in check: essential and synergistic functions of Mdm2 and Mdm4
Marine, J.-C., Francoz, S., Maetens, M., Wahl, G., Toledo, F., & Lozano, G. (2006) · Cell Death & Differentiation · doi:10.1038/sj.cdd.4401912 · Cited by 352
p53 — a Jack of all trades but master of none
Junttila, M. R., & Evan, G. I. (2009) · Nature Reviews Cancer · doi:10.1038/nrc2728 · Cited by 345
A dual role of p53 in the control of autophagy
Tasdemir, E., Maiuri, M. C., Morselli, E., Criollo, A., D'Amelio, M., Djavaheri-Mergny, M., Cecconi, F., Tavernarakis, N., & Kroemer, G. (2008) · Autophagy · doi:10.4161/auto.6486 · Cited by 345
A p53-dependent mechanism underlies macrocytic anemia in a mouse model of human 5q– syndrome
Barlow, J. L., Drynan, L. F., Hewett, D. R., Holmes, L. R., Lorenzo-Abalde, S., Lane, A. L., Jolin, H. E., Pannell, R., Middleton, A. J., Wong, S. H., et al. (2010) · Nature Medicine · doi:10.1038/nm.2063 · Cited by 334
Migliorini, D., Denchi, E. L., Danovi, D., Jochemsen, A., Capillo, M., Gobbi, A., Helin, K., Pelicci, P. G., & Marine, J.-C. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.15.5527-5538.2002 · Cited by 313
Linke, K., Mace, P. D., Smith, C. A., Vaux, D. L., Silke, J., & Day, C. L. (2008) · Cell Death & Differentiation · doi:10.1038/sj.cdd.4402309 · Cited by 288
Mutant p53 protein localized in the cytoplasm inhibits autophagy
Morselli, E., Tasdemir, E., Chiara Maiuri, M., Galluzzi, L., Kepp, O., Criollo, A., Vicencio, J. M., Soussi, T., & Kroemer, G. (2008) · Cell Cycle · doi:10.4161/cc.7.19.6751 · Cited by 277
The promises and perils of p53
Krizhanovsky, V., & Lowe, S. W. (2009) · Nature · doi:10.1038/4601085a · Cited by 274
Osteoblast differentiation and skeletal development are regulated by Mdm2–p53 signaling
Lengner, C. J., Steinman, H. A., Gagnon, J., Smith, T. W., Henderson, J. E., Kream, B. E., Stein, G. S., Lian, J. B., & Jones, S. N. (2006) · The Journal of Cell Biology · doi:10.1083/jcb.200508130 · Cited by 265
Inhibition of tumor angiogenesis by p53: a new role for the guardian of the genome
Teodoro, J. G., Evans, S. K., & Green, M. R. (2007) · Journal of Molecular Medicine · doi:10.1007/s00109-007-0221-2 · Cited by 260
Marine, J.-C. W., Dyer, M. A., & Jochemsen, A. G. (2007) · Journal of Cell Science · doi:10.1242/jcs.03362 · Cited by 228
Wang, X., Kua, H.-Y., Hu, Y., Guo, K., Zeng, Q., Wu, Q., Ng, H.-H., Karsenty, G., de Crombrugghe, B., Yeh, J., et al. (2006) · The Journal of Cell Biology · doi:10.1083/jcb.200507106 · Cited by 225
p53 inhibitors preserve dopamine neurons and motor function in experimental parkinsonism
Duan, W., Zhu, X., Ladenheim, B., Yu, Q., Guo, Z., Oyler, J., Cutler, R. G., Cadet, J. L., Greig, N. H., & Mattson, M. P. (2002) · Annals of Neurology · doi:10.1002/ana.10350 · Cited by 204
Toledo, F., Krummel, K. A., Lee, C. J., Liu, C.-W., Rodewald, L.-W., Tang, M., & Wahl, G. M. (2006) · Cancer Cell · doi:10.1016/j.ccr.2006.03.014 · Cited by 199 · cited 1×
“…domains, between residues 60-95, lies the proline-rich domain (PRD), which was originally proposed to participate in protein-protein interactions on the basis of the presence of PxxP motifs that resemble Src homology 3 (SH3)-domainbinding regions (Toledo et al., 2006; Toledo et al., 2007).”
BackgroundSingle-nucleotide polymorphisms in the p53 pathway regulate fertility in humans
Kang, H.-J., Feng, Z., Sun, Y., Atwal, G., Murphy, M. E., Rebbeck, T. R., Rosenwaks, Z., Levine, A. J., & Hu, W. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0904280106 · Cited by 193
p53‐dependent neuronal cell death in a DJ‐1‐deficient zebrafish model of Parkinson's disease
Bretaud, S., Allen, C., Ingham, P. W., & Bandmann, O. (2007) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2006.04291.x · Cited by 191
Krummel, K. A., Lee, C. J., Toledo, F., & Wahl, G. M. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0503068102 · Cited by 187
Mammalian macroautophagy at a glance
Ravikumar, B., Futter, M., Jahreiss, L., Korolchuk, V. I., Lichtenberg, M., Luo, S., Massey, D. C. O., Menzies, F. M., Narayanan, U., Renna, M., et al. (2009) · Journal of Cell Science · doi:10.1242/jcs.031773 · Cited by 183
20 years studying p53 functions in genetically engineered mice
Donehower, L. A., & Lozano, G. (2009) · Nature Reviews Cancer · doi:10.1038/nrc2731 · Cited by 168
Transcriptional repression mediated by the p53 tumour suppressor
Ho, J., & Benchimol, S. (2003) · Cell Death & Differentiation · doi:10.1038/sj.cdd.4401191 · Cited by 166
p53 Plays a Role in Mesenchymal Differentiation Programs, in a Cell Fate Dependent Manner
Molchadsky, A., Shats, I., Goldfinger, N., Pevsner-Fischer, M., Olson, M., Rinon, A., Tzahor, E., Lozano, G., Zipori, D., Sarig, R., et al. (2008) · PLoS ONE · doi:10.1371/journal.pone.0003707 · Cited by 161
p53-dependent cell death signaling in neurons
Morrison, R. S., Kinoshita, Y., Johnson, M. D., Guo, W., & Garden, G. A. (2003) · Neurochemical Research · doi:10.1023/a:1021687810103 · Cited by 158
p53 ancestry: gazing through an evolutionary lens
Lu, W.-J., Amatruda, J. F., & Abrams, J. M. (2009) · Nature reviews. Cancer · doi:10.1038/nrc2732 · Cited by 112
Structural Biology of the Tumor Suppressor p53 and Cancer‐Associated Mutants
(2007) · Advances in Cancer Research · doi:10.1016/s0065-230x(06)97001-8 · Cited by 106
The Arf/p53 pathway in cancer and aging
Matheu, A., Maraver, A., & Serrano, M. (2008) · Cancer Research · doi:10.1158/0008-5472.can-07-6851 · Cited by 105
Bauer, J. H., Poon, P. C., Glatt-Deeley, H., Abrams, J. M., & Helfand, S. L. (2005) · Current Biology · doi:10.1016/j.cub.2005.10.051 · Cited by 100
Ruzankina, Y., Schoppy, D. W., Asare, A., Clark, C. E., Vonderheide, R. H., & Brown, E. J. (2009) · Nature Genetics · doi:10.1038/ng.441 · Cited by 97
The interaction of p53 with replication protein A mediates suppression of homologous recombination
Romanova, L. Y., Willers, H., Blagosklonny, M. V., & Powell, S. N. (2004) · Oncogene · doi:10.1038/sj.onc.1207982 · Cited by 95
Delayed treatment with a p53 inhibitor enhances recovery in stroke brain
Luo, Y., Kuo, C., Shen, H., Chou, J., Greig, N. H., Hoffer, B. J., & Wang, Y. (2009) · Annals of Neurology · doi:10.1002/ana.21592 · Cited by 94
Begus-Nahrmann, Y., Lechel, A., Obenauf, A. C., Nalapareddy, K., Peit, E., Hoffmann, E., Schlaudraff, F., Liss, B., Schirmacher, P., Kestler, H., et al. (2009) · Nature Genetics · doi:10.1038/ng.426 · Cited by 88
In vivo analysis of p53 tumor suppressor function using genetically engineered mouse models
Broz, D. K., & Attardi, L. D. (2010) · Carcinogenesis · doi:10.1093/carcin/bgp331 · Cited by 67
Self-citationReduced expression of the Caenorhabditis elegans p53 ortholog cep-1 results in increased longevity
Arum, O., & Johnson, T. E. (2007) · The Journals of Gerontology Series A: Biological Sciences and Medical Sciences · doi:10.1093/gerona/62.9.951 · Cited by 64
Liu, P., Xu, B., Cavalieri, T. A., & Hock, C. E. (2006) · Shock · doi:10.1097/01.shk.0000232273.11225.af · Cited by 56
Multivalent binding of p53 to the STAGA complex mediates coactivator recruitment after UV damage
Gamper, A. M., & Roeder, R. G. (2008) · Molecular and Cellular Biology · doi:10.1128/mcb.01461-07 · Cited by 55
Involvement of stromal p53 in tumor-stroma interactions
Bar, J., Moskovits, N. B.-C., & Oren, M. (2009) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2009.11.006 · Cited by 49
Toledo, F., Lee, C. J., Krummel, K. A., Rodewald, L.-W., Liu, C.-W., & Wahl, G. M. (2007) · Molecular and Cellular Biology · doi:10.1128/mcb.00999-06 · Cited by 46
Lessons from p53 in non-mammalian models
Lu, W.-J., & Abrams, J. M. (2006) · Cell Death & Differentiation · doi:10.1038/sj.cdd.4401922 · Cited by 42
Stem cells: The promises and perils of p53
Krizhanovsky, V., & Lowe, S. W. (2009) · Nature · doi:10.1038/nature08367 · Cited by 21
Sliding into home: facilitated p53 search for targets by the basic DNA binding domain
Liu, Y., & Kulesz-Martin, M. F. (2006) · Cell Death & Differentiation · doi:10.1038/sj.cdd.4401905 · Cited by 17
(2002) · PubMed
Cited by
Unravelling mechanisms of p53-mediated tumour suppression
Bieging, K. T., Mello, S. S., & Attardi, L. D. (2014) · Nature Reviews Cancer · doi:10.1038/nrc3711 · Cited by 1,387
Self-citationDistinct 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
Self-citationO-GlcNAc signalling: implications for cancer cell biology
Slawson, C., & Hart, G. W. (2011) · Nature Reviews Cancer · doi:10.1038/nrc3114 · Cited by 458
Ubiquitylation in apoptosis: a post-translational modification at the edge of life and death
Vucic, D., Dixit, V. M., & Wertz, I. E. (2011) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3143 · Cited by 444
The Therapeutic Target Hsp90 and Cancer Hallmarks
Miyata, Y., Nakamoto, H., & Neckers, L. (2013) · Current Pharmaceutical Design · doi:10.2174/138161213804143725 · Cited by 352
Metadata
- Authors
- Brady, C. A., & Attardi, L. D.
- Affiliations
- Stanford Medicine (US)
- Corresponding author
- Attardi, Laura D.
- Venue
- Journal of Cell Science
- Publisher
- The Company of Biologists
- Published
- 2010-08-01
- Volume
- 123
- Issue
- 15
- Pages
- 2527-2532
- ISSN
- 0021-9533 (ISSN-L)
- 1477-9137
- PMC
- PMC2912460
- OpenAlex
- W2170622332
- Cited by
- 403
- References
- 96
- Citations by year
- 2026: 13 · 2025: 16 · 2024: 19 · 2023: 28 · 2022: 17 · 2021: 24 · 2020: 29 · 2019: 39 · 2018: 32 · 2017: 28 · 2016: 22 · 2015: 27 · 2014: 33 · 2013: 26 · 2012: 27
- FWCI
- 2.93
- Type
- journal article
- Language
- en
- Open access
- green
- pmc.ncbi.nlm.nih.gov
- Locations
- Journal of Cell Science (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- p53, tumor suppressor, TP53 mutation, Li-Fraumeni syndrome, cell cycle arrest, apoptosis, cellular stress response, DNA damage, hypoxia, oncogene-induced senescence, autophagy, cellular metabolism, oxidative stress, p53-null mice, cancer susceptibility
- MeSH terms
- Animals, Autophagy, Cytoplasm, Humans, Neoplasms, Transcriptional Activation, Tumor Suppressor Protein p53, Apoptosis, Proto-Oncogene Proteins c-mdm2
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.
A language model drew the claims from the paper on 2026-11-15, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-11-15 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (qwen3.8-omni-flash).
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
Data sources
Bibliographic data: Semantic Scholar, OpenAlex, Crossref.
Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
