Cited by 371Cancer-related Molecular PathwaysHeat shock proteins researchCell death mechanisms and regulation

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Design of a synthetic Mdm2-binding mini protein that activates the p53 response in vivo

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Böttger, Angelika, Böttger, Volker, Sparks, Alison, Liu, Wei-Li, Howard, Stephanie F., Lane, David P.·1997·Current Biology

DOI 10.1016/s0960-9822(06)00374-5

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Abstract

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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BindingDB Entry 3318: Novel 1,4-benzodiazepine-2,5-diones as Hdm2 antagonists with improved cellular activity
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BindingDB Entry 50043814: Substituted piperidines as HDM2 inhibitors.
BindingDB (2014) · UC San Diego · doi:10.7270/q2765gt9
BindingDB Entry 50042883: Rational design and binding mode duality of MDM2-p53 inhibitors.
BindingDB (2013) · UC San Diego · doi:10.7270/q2hd7x1p
Cellular senescence and cancer
(1999) · doi:10.1002/(sici)1096-9896(199901)187:1

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.
ORCID: Böttger, Angelika
Lane, David P.
Venue: Current Biology
Publisher: Elsevier BV
Published: 1997-11
Volume: 7
Issue: 11
Pages: 860-869
ISSN: 0960-9822 (ISSN-L)
DOI: 10.1016/s0960-9822(06)00374-5
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: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 5737 d)
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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Design of a synthetic Mdm2-binding mini protein that activates the p53 response in vivo

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