title: Understanding the function-structure and function-mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis.
abstract: Inactivation of the tumor suppressor p53 by missense mutations is the most frequent genetic alteration in human cancers. The common missense mutations in the TP53 gene disrupt the ability of p53 to bind to DNA and consequently to transactivate downstream genes. However, it is still not fully understood how a large number of the remaining mutations affect p53 structure and function. Here, we used a comprehensive site-directed mutagenesis technique and a yeast-based functional assay to construct, express, and evaluate 2,314 p53 mutants representing all possible amino acid substitutions caused by a point mutation throughout the protein (5.9 substitutions per residue), and correlated p53 function with structure- and tumor-derived mutations. This high-resolution mutation analysis allows evaluation of previous predictions and hypotheses through interrelation of function, structure and mutation.
authors.affiliation: Department of Clinical Oncology, Institute of Development, Aging, and Cancer, Tohoku University, Sendai 980-8575, Japan.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Kato
authors.forename: Shuang-Yin
authors.initials: SY
authors.lastname: Han
authors.forename: Wen
authors.initials: W
authors.lastname: Liu
authors.forename: Kazunori
authors.initials: K
authors.lastname: Otsuka
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Shibata
authors.forename: Ryunosuke
authors.initials: R
authors.lastname: Kanamaru
authors.forename: Chikashi
authors.initials: C
authors.lastname: Ishioka
mesh_terms: D019943:Amino Acid Substitution; D004260:DNA Repair; D017930:Genes, Reporter; D016158:Genes, p53; D006801:Humans; D008156:Luciferases / Q000032:analysis / Q000235:genetics; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D020125:Mutation, Missense; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000502:physiology; D012441:Saccharomyces cerevisiae / Q000235:genetics; D013329:Structure-Activity Relationship; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000502:physiology*
chemical_list: D011993:Recombinant Fusion Proteins; D016159:Tumor Suppressor Protein p53; D008156:Luciferases