Small peptides activate the latent sequence-specific DNA binding function of p53.
Normal cells contain p53 protein in a latent state that can be activated for sequence-specific transcription by low levels of UV radiation without an increase in protein levels. Microinjection of cells with an antibody specific to the C-terminal negative regulatory domain can activate the function of p53 as a specific transcription factor in the absence of irradiation damage, suggesting that posttranslational modification of a negative regulatory domain in vivo is a rate-limiting step for p53 activation. Small peptides derived from the negative regulatory domain of p53 have been used as biochemical tools to distinguish between allosteric and steric mechanisms of negative regulation of p53 tetramer activity. Presented is the development of a highly specific peptide activation system that is consistent with an allosteric mechanism of negative regulation and that forms a precedent for the synthesis of novel low molecular mass modifiers of the p53 response.
Hupp
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Department of Biochemistry, Dundee University, Scotland.
Sparks
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Lane
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D000494:Allosteric Regulation; D000595:Amino Acid Sequence; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D047390:Casein Kinase II; D004247:DNA / Q000378:metabolism; D004357:Drug Synergism; D004797:Enzyme-Linked Immunosorbent Assay; D029968:Escherichia coli Proteins; D018840:HSP70 Heat-Shock Proteins / Q000494:pharmacology; D051379:Mice; D008954:Models, Biological; D008956:Models, Chemical; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000494:pharmacology; D017384:Sequence Deletion; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic / Q000187:drug effects / Q000528:radiation effects; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D014466:Ultraviolet Rays
D000906:Antibodies; D029968:Escherichia coli Proteins; D018840:HSP70 Heat-Shock Proteins; D009842:Oligopeptides; D016159:Tumor Suppressor Protein p53; D004247:DNA; D047390:Casein Kinase II; D017346:Protein Serine-Threonine Kinases; C063842:dnaK protein, E coli