The DOI matches its Crossref record; 30 of the 37 references it cites were found in a registry or an index.
Design of a synthetic Mdm2-binding mini protein that activates the p53 response in vivo
Open accessAbstract
Background The transcriptional activation function of the p53 tumour suppressor protein is induced by DNA damage and results in growth arrest and/or apoptotic responses. A key component of this response is the dramatic rise in p53 protein concentration resulting from an increase in the protein's stability. Very recently, it has been suggested that interaction with the Mdm2 protein may target p53 for rapid degradation. We have designed a gene encoding a small protein that binds tightly to the p53-binding pocket on the Mdm2 protein. We have constructed the gene by cloning a phage display optimised Mdm2-binding peptide into the active-site loop of thioredoxin. Results When introduced into cells containing low levels of wild-type p53, this protein causes a striking accumulation of the endogenous p53 protein, activation of a p53-responsive reporter gene, and cell cycle arrest mimicking the effects seen in these cells after exposure to UV or ionising radiation. Microinjection of a monoclonal antibody to the p53-binding site on Mdm2 achieves a similar effect, establishing its specificity. Conclusions These results demonstrate that the p53 response is constitutively regulated in normal cells by Mdm2 and that disruption of the interaction alone is sufficient to stabilise the p53 protein and activate the p53 response. Our mini protein approach provides a powerful new method to activate p53 without causing DNA damage. More broadly, it establishes a powerful general method for determinin…
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Metadata
- Authors
- Böttger, A., Böttger, V., Sparks, A., Liu, W.-L., Howard, S. F., & Lane, D. P.
- Affiliations
- University of Dundee (GB)
- Corresponding author
- Lane, David P.
- Venue
- Current Biology
- Publisher
- Elsevier BV
- Published
- 1997-11
- Volume
- 7
- Issue
- 11
- Pages
- 860-869
- ISSN
- 0960-9822 (ISSN-L)
- OpenAlex
- W2041568308
- Cited by
- 363
- References
- 37
- Citations by year
- 2024: 1 · 2023: 2 · 2022: 5 · 2021: 2 · 2020: 7 · 2019: 5 · 2018: 3 · 2017: 7 · 2016: 2 · 2015: 4 · 2014: 12 · 2013: 6 · 2012: 12
- FWCI
- 11.86
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Current Biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- European Commission
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- p53, MDM2, p53-MDM2 interaction, protein-protein interaction disruption, thioredoxin, p53 stabilization, transcriptional activation, cell cycle arrest, phage display peptides, DNA damage response, tumour suppressor
- MeSH terms
- Amino Acid Sequence, Animals, Binding, Competitive, Cell Cycle, Cell Line, Humans, Male, Molecular Sequence Data, Nuclear Proteins, Prostate, Protein Binding, Proto-Oncogene Proteins, Recombinant Fusion Proteins, Thioredoxins, Transfection, Tumor Cells, Cultured, Protein Engineering, Transcriptional Activation, Tumor Suppressor Protein p53, Mice, Proto-Oncogene Proteins c-mdm2
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