DNA Binding Cooperativity of p53 Modulates the Decision between Cell-Cycle Arrest and Apoptosis
Open accessAbstract
p53 limits the proliferation of precancerous cells by inducing cell-cycle arrest or apoptosis. How the decision between survival and death is made at the level of p53 binding to target promoters remains unclear. Using cancer cell lines, we show that the cooperative nature of DNA binding extends the binding spectrum of p53 to degenerate response elements in proapoptotic genes. Mutational inactivation of cooperativity therefore does not compromise the cell-cycle arrest response but strongly reduces binding of p53 to multiple proapoptotic gene promoters (BAX, PUMA, NOXA, CASP1). Vice versa, engineered mutants with increased cooperativity show enhanced binding to proapoptotic genes, which shifts the cellular response to cell death. Furthermore, the cooperativity of DNA binding determines the extent of apoptosis in response to DNA damage. Because mutations, which impair cooperativity, are genetically linked to cancer susceptibility in patients, DNA binding cooperativity contributes to p53's tumor suppressor activity.
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?
The transactivation of target genes requires cooperative interaction between the p53 molecules at DNA response elements.
“The p53 transcription factor uses two transactivation domains to drive gene expression58 and the transactivation of target genes requires cooperative interaction between the p53 molecules at DNA REs.23, 59”
From Census and evaluation of p53 target genes (2017) · cites this paper as [59]
Cites
Live or let die: the cell's response to p53
Vousden, K. H., & Lü, X. (2002) · Nature reviews. Cancer · doi:10.1038/nrc864 · Cited by 3,177 · see citing works
Crystal Structure of a p53 Tumor Suppressor-DNA Complex: Understanding Tumorigenic Mutations
Cho, Y., Gorina, S., Jeffrey, P. D., & Pavletich, N. P. (1994) · Science · doi:10.1126/science.8023157 · Cited by 2,559 · cited 4× · see citing works
“already indicated that the assembly of four core domains on a straight DNA strand with the experimentally predicted C2 symmetry would be accompanied by steric hindrance between the H1 helices (Cho et al., 1994).”
BackgroundInfluentialVousden, K. H., & Lane, D. P. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2147 · Cited by 2,275 · see citing works
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 · see citing works
DNA sequence-dependent deformability deduced from protein–DNA crystal complexes
Olson, W. K., Gorin, A. A., Lu, X., Hock, L. M., & Zhurkin, V. B. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.19.11163 · Cited by 1,039 · see citing works
Acetylation of the p53 DNA-binding domain regulates apoptosis induction.
Sykes, S. M., Mellert, H. S., Holbert, M. A., Li, K., Marmorstein, R., Lane, W. S., & McMahon, S. B. (2006) · Molecular Cell · doi:10.1016/j.molcel.2006.11.026 · Cited by 752 · see citing works
Tip60-Dependent Acetylation of p53 Modulates the Decision between Cell-Cycle Arrest and Apoptosis
Tang, Y., Luo, J., Zhang, W., & Gu, W. J. (2006) · Molecular Cell · doi:10.1016/j.molcel.2006.11.021 · Cited by 724 · see citing works
Homeodomain-interacting protein kinase-2 phosphorylates p53 at Ser 46 and mediates apoptosis
D’Orazi, G., Cecchinelli, B., Bruno, T., Manni, I., Higashimoto, Y., Saito, S., Gostissa, M., Coen, S., Marchetti, A., Sal, G. D., et al. (2001) · Nature Cell Biology · doi:10.1038/ncb714 · Cited by 682 · see citing works
ASPP Proteins Specifically Stimulate the Apoptotic Function of p53
Samuels-Lev, Y., O'Connor, D. J., Bergamaschi, D., Trigiante, G., Hsieh, J.-K., Zhong, S., Campargue, I., Naumovski, L., Crook, T., & Lu, X. (2001) · Molecular Cell · doi:10.1016/s1097-2765(01)00367-7 · Cited by 664 · see citing works
Dissecting p53-dependent apoptosis
Chipuk, J. E., & Green, D. R. (2006) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4401908 · Cited by 452 · see citing works
Structural Basis of DNA Recognition by p53 Tetramers
Kitayner, M., Rozenberg, H., Kessler, N., Rabinovich, D., Shaulov, L., Haran, T. E., & Shakked, Z. (2006) · Molecular Cell · doi:10.1016/j.molcel.2006.05.015 · Cited by 408 · see citing works
The p53 family in differentiation and tumorigenesis
Stiewe, T. (2007) · Nature Reviews Cancer · doi:10.1038/nrc2072 · Cited by 306 · see citing works
Self-citationTaira, N., Nihira, K., Yamaguchi, T., Miki, Y., & Yoshida, K. (2007) · Molecular Cell · doi:10.1016/j.molcel.2007.02.007 · Cited by 299 · see citing works
Differential Activation of Target Cellular Promoters by p53 Mutants with Impaired Apoptotic Function
Ludwig, R. L., Bates, S., & Vousden, K. H. (1996) · Molecular and Cellular Biology · doi:10.1128/mcb.16.9.4952 · Cited by 275 · see citing works
Cooperative Binding of Tetrameric p53 to DNA
Weinberg, R. L., Veprintsev, D. B., & Fersht, A. R. (2004) · Journal of Molecular Biology · doi:10.1016/j.jmb.2004.06.071 · Cited by 251 · see citing works
Comparative Binding of p53 to its Promoter and DNA Recognition Elements
Weinberg, R. L., Veprintsev, D. B., Bycroft, M., & Fersht, A. R. (2005) · Journal of Molecular Biology · doi:10.1016/j.jmb.2005.03.014 · Cited by 206 · see citing works
Quaternary structures of tumor suppressor p53 and a specific p53–DNA complex
Tidow, H., Melero, R., Mylonas, E., Freund, S. M. V., Großmann, J., Carazo, J. M., Svergun, D. I., Valle, M., & Fersht, A. R. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0705069104 · Cited by 182 · see citing works
Hzf Determines Cell Survival upon Genotoxic Stress by Modulating p53 Transactivation
Das, S., Raj, L., Zhao, B., Kimura, Y., Bernstein, A., Aaronson, S. A., & Lee, S. W. (2007) · Cell · doi:10.1016/j.cell.2007.06.013 · Cited by 160 · see citing works
Mantovani, F., Tocco, F., Girardini, J. E., Smith, P., Gasco, M., Lü, X., Crook, T., & Sal, G. D. (2007) · Nature Structural & Molecular Biology · doi:10.1038/nsmb1306 · Cited by 150 · see citing works
Four p53 DNA-binding domain peptides bind natural p53-response elements and bend the DNA.
Balagurumoorthy, P., Sakamoto, H., Lewis, M. S., Zambrano, N., Clore, G. M., Gronenborn, A. M., Appella, E., & Harrington, R. E. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.19.8591 · Cited by 126 · see citing works
The structure of p53 tumour suppressor protein reveals the basis for its functional plasticity
Okorokov, A. L., Sherman, M. B., Plisson‐Chastang, C., Grinkevich, V. V., Sigmundsson, K., Selivanova, G., Milner, J., & Orlova, E. V. (2006) · The EMBO Journal · doi:10.1038/sj.emboj.7601382 · Cited by 125 · see citing works
p53 family members in myogenic differentiation and rhabdomyosarcoma development
Çam, H., Griesmann, H., Beitzinger, M., Hofmann, L., Beinoravičiūtė-Kellner, R., Sauer, M., Hüttinger-Kirchhof, N., Oswald, C., Friedl, P., Gattenlöhner, S., et al. (2006) · Cancer Cell · doi:10.1016/j.ccr.2006.08.024 · Cited by 109 · see citing works
Self-citationCore domain interactions in full-length p53 in solution
Veprintsev, D. B., Freund, S. M. V., Andreeva, A., Rutledge, S. E., Tidow, H., Cañadillas, J. M. P., Blair, C. M., & Fersht, A. R. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0511130103 · Cited by 95 · see citing works
Klein, C., Planker, E., Diercks, T., Kessler, H., Künkele, K., Lang, K., Hansen, S., & Schwaiger, M. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m107516200 · Cited by 86 · see citing works
Dehner, A., Klein, C., Hansen, S., Müller, L., Büchner, J., Schwaiger, M., & Kessler, H. (2005) · Angewandte Chemie International Edition · doi:10.1002/anie.200501887 · Cited by 52 · see citing works
Ma, B., & Levine, A. J. (2007) · Nucleic Acids Research · doi:10.1093/nar/gkm890 · Cited by 34 · see citing works
Identification of p53–46F as a super p53 with an enhanced ability to induce p53‐dependent apoptosis
Nakamura, Y., Futamura, M., Kamino, H., et al. (2006) · Cancer Science · doi:10.1111/j.1349-7006.2006.00214.x · Cited by 31 · see citing works
Atomic force microscopy reveals kinks in the p53 response element DNA
Balagurumoorthy, P., Lindsay, S., & Harrington, R. E. (2002) · Biophysical Chemistry · doi:10.1016/s0301-4622(02)00169-2 · Cited by 22 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
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
The multiple mechanisms that regulate p53 activity and cell fate
Hafner, A., Bulyk, M. L., Jambhekar, A., & Lahav, G. (2019) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-019-0110-x · Cited by 1,129 · see citing works
P53 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
Census and evaluation of p53 target genes
Fischer, M. (2017) · Oncogene · doi:10.1038/onc.2016.502 · Cited by 971 · see citing works
Translating p53 into the clinic
Cheok, C. F., Verma, C. S., Baselga, J., & Lane, D. P. (2011) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2010.174 · Cited by 381 · see citing works
Schlereth, K., Heyl, C., Krampitz, A.-M., Mernberger, M., Finkernagel, F., Scharfe, M., Jarek, M., Leich, E., Rosenwald, A., & Stiewe, T. (2013) · PLoS Genetics · doi:10.1371/journal.pgen.1003726 · Cited by 87 · see citing works
Self-citationWhole-genome cartography of p53 response elements ranked on transactivation potential
Tebaldi, T., Zaccara, S., Alessandrini, F., Bisio, A., Ciribilli, Y., & Inga, A. (2015) · BMC Genomics · doi:10.1186/s12864-015-1643-9 · Cited by 72 · see citing works
- Authors
- Schlereth, K., Beinoraviciute-Kellner, R., Zeitlinger, M. K., Bretz, A. C., Sauer, M., Charles, J. P., Vogiatzi, F., Leich, E., Samans, B., Eilers, M., Kisker, C., Rosenwald, A., & Stiewe, T.
- Affiliations
- Philipps University of Marburg (DE)
- University of Würzburg (DE)
- Corresponding author
- Stiewe, Thorsten
- ORCID
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2010-05
- Volume
- 38
- Issue
- 3
- Pages
- 356-368
- ISSN
- 1097-2765 (ISSN-L)
- OpenAlex
- W2037147972
- Cited by
- 113
- References
- 28
- Citations by year
- 2026: 8 · 2025: 3 · 2024: 6 · 2023: 10 · 2022: 9 · 2021: 10 · 2020: 7 · 2019: 7 · 2018: 5 · 2017: 4 · 2016: 3 · 2015: 8 · 2014: 8 · 2013: 8 · 2012: 8
- FWCI
- 3.96
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 1173 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- Deutsche Krebshilfe
- 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 › DNA Repair Mechanisms
- Keywords
- p53, DNA binding cooperativity, cell cycle arrest, apoptosis, Bax, PUMA, Noxa, caspase-1, DNA damage response, tumor suppressor activity, cancer susceptibility, mutant p53
- MeSH terms
- Binding Sites, Cell Cycle, DNA, DNA Damage, Humans, Models, Molecular, Mutation, Promoter Regions, Genetic, Protein Conformation, Time Factors, Transfection, Gene Expression Regulation, Neoplastic, Tumor Suppressor Protein p53, Mutagenesis, Site-Directed, Apoptosis, Gene Expression Profiling, HCT116 Cells, Cell Proliferation, Apoptosis Regulatory Proteins
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
