title: Mutations in serines 15 and 20 of human p53 impair its apoptotic activity.
abstract: Phosphorylation of the p53 tumor suppressor protein is likely to play an important role in regulating its activity. To study the regulatory role of potential phosphorylation sites within the N-terminal transactivation domain of human p53 (hp53), a series of p53 serine mutants were evaluated for transcriptional transactivation and sequence specific DNA binding. The role of these mutations in regulating p53-mediated growth suppression and programmed cell death was examined. This mutational analysis comprised serine residues located at positions 6, 9, 15, 20, 33 and 37 of human p53. Substitution of serine for alanine, either at individual residues or at all six residues together, did not affect the suppression of cell growth and cell transformation, or the ability to bind DNA specifically and to transactivate different promoters, nor did it alter p53 expression. However, the ability of p53 to induce apoptosis was impaired by specific serine substitutions. Mutations in all six N-terminal serines together reduced the apoptotic activity of p53 in H1299 cells by 50%. Analysis of individual mutants revealed that mutations in serine 15 and 20 are primarily responsible for this impairment. Our results suggest that these serines play a role in the regulation of p53-mediated apoptosis.
authors.affiliation: Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot, Israel.
authors.forename: T
authors.initials: T
authors.lastname: Unger
authors.forename: R V
authors.initials: RV
authors.lastname: Sionov
authors.forename: E
authors.initials: E
authors.lastname: Moallem
authors.forename: C L
authors.initials: CL
authors.lastname: Yee
authors.forename: P M
authors.initials: PM
authors.lastname: Howley
authors.forename: M
authors.initials: M
authors.lastname: Oren
authors.forename: Y
authors.initials: Y
authors.lastname: Haupt
mesh_terms: D000409:Alanine / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D001665:Binding Sites; D002471:Cell Transformation, Neoplastic; D004247:DNA / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D051379:Mice; D016297:Mutagenesis, Site-Directed; D012694:Serine / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D016159:Tumor Suppressor Protein p53; D012694:Serine; D004247:DNA; D000409:Alanine