title: Molecular basis for modulation of the p53 target selectivity by KLF4.
abstract: The tumour suppressor p53 controls transcription of various genes involved in apoptosis, cell-cycle arrest, DNA repair and metabolism. However, its DNA-recognition specificity is not nearly sufficient to explain binding to specific locations in vivo. Here, we present evidence that KLF4 increases the DNA-binding affinity of p53 through the formation of a loosely arranged ternary complex on DNA. This effect depends on the distance between the response elements of KLF4 and p53. Using nuclear magnetic resonance and fluorescence techniques, we found that the amino-terminal domain of p53 interacts with the KLF4 zinc fingers and mapped the interaction site. The strength of this interaction was increased by phosphorylation of the p53 N-terminus, particularly on residues associated with regulation of cell-cycle arrest genes. Taken together, the cooperative binding of KLF4 and p53 to DNA exemplifies a regulatory mechanism that contributes to p53 target selectivity.
authors.affiliation: Medical Research Council Laboratory of Molecular Biology, Cambridge, United Kingdom.
authors.forename: Tobias
authors.initials: T
authors.lastname: Brandt
authors.forename: Fiona M
authors.initials: FM
authors.lastname: Townsley
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Teufel
authors.forename: Stefan M V
authors.initials: SM
authors.lastname: Freund
authors.forename: Dmitry B
authors.initials: DB
authors.lastname: Veprintsev
mesh_terms: D019295:Computational Biology; D004247:DNA / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D010766:Phosphorylation; D011485:Protein Binding; D021381:Protein Transport; D020218:Response Elements / Q000235:genetics; D013379:Substrate Specificity; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D016335:Zinc Fingers
chemical_list: C000715467:KLF4 protein, human; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D016159:Tumor Suppressor Protein p53; D004247:DNA