title: p53 DNA binding cooperativity is essential for apoptosis and tumor suppression in vivo.
abstract: Four molecules of the tumor suppressor p53 assemble to cooperatively bind proapoptotic target genes. The structural basis for cooperativity consists of interactions between adjacent DNA binding domains. Mutations at the interaction interface that compromise cooperativity were identified in cancer patients, suggesting a requirement of cooperativity for tumor suppression. We report on an analysis of cooperativity mutant p53E177R mice. Apoptotic functions of p53 triggered by DNA damage and oncogenes were abolished in these mice, whereas functions in cell-cycle control, senescence, metabolism, and antioxidant defense were retained and were sufficient to suppress development of spontaneous T cell lymphoma. Cooperativity mutant mice are nevertheless highly cancer prone and susceptible to different oncogene-induced tumors. Our data underscore the relevance of DNA binding cooperativity for p53-dependent apoptosis and tumor suppression and highlight cooperativity mutations as a class of p53 mutations that result in a selective loss of apoptotic functions due to an altered quaternary structure of the p53 tetramer.
authors.affiliation: Department of Molecular Oncology, University of Marburg, 35032 Marburg, Germany.
authors.forename: Oleg
authors.initials: O
authors.lastname: Timofeev
authors.forename: Katharina
authors.initials: K
authors.lastname: Schlereth
authors.forename: Michael
authors.initials: M
authors.lastname: Wanzel
authors.forename: Attila
authors.initials: A
authors.lastname: Braun
authors.forename: Bernhard
authors.initials: B
authors.lastname: Nieswandt
authors.forename: Axel
authors.initials: A
authors.lastname: Pagenstecher
authors.forename: Andreas
authors.initials: A
authors.lastname: Rosenwald
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Elsässer
authors.forename: Thorsten
authors.initials: T
authors.lastname: Stiewe
mesh_terms: D000375:Aging; D000483:Alleles; D000818:Animals; D017209:Apoptosis; D059447:Cell Cycle Checkpoints; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism*; D004249:DNA Damage; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D055879:Gene Knock-In Techniques; D018095:Germ-Line Mutation; D006579:Heterozygote; D008223:Lymphoma / Q000209:etiology; D051379:Mice; D018345:Mice, Knockout; D011485:Protein Binding; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D016159:Tumor Suppressor Protein p53; D004247:DNA