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p53 DNA Binding Cooperativity Is Essential for Apoptosis and Tumor Suppression In Vivo
Zitieren Sie bitte immer diese URN: urn:nbn:de:bvb:20-opus-122168
- 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 p53(E177R) mice. Apoptotic functions of p53 triggered by DNA damage and oncogenes were abolished in these mice, whereasFour 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 p53(E177R) 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.…
Autor(en): | Oleg Timofeev, Katharina Schlereth, Michael Wanzel, Attila Braun, Bernhard Nieswandt, Axel Pagenstecher, Andreas Rosenwald, Hans-Peter Elsässer, Thorsten Stiewe |
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URN: | urn:nbn:de:bvb:20-opus-122168 |
Dokumentart: | Artikel / Aufsatz in einer Zeitschrift |
Institute der Universität: | Medizinische Fakultät / Pathologisches Institut |
Fakultät für Biologie / Rudolf-Virchow-Zentrum | |
Sprache der Veröffentlichung: | Englisch |
Titel des übergeordneten Werkes / der Zeitschrift (Englisch): | Cell Reports |
Erscheinungsjahr: | 2013 |
Band / Jahrgang: | 3 |
Seitenangabe: | 1512-1525 |
Originalveröffentlichung / Quelle: | Cell Reports 3, 1512–1525, May 30, 2013. doi:10.1016/j.celrep.2013.04.008 |
DOI: | https://doi.org/10.1016/j.celrep.2013.04.008 |
Allgemeine fachliche Zuordnung (DDC-Klassifikation): | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 616 Krankheiten |
Freie Schlagwort(e): | antioxidant function; cell-cycle arrest; damage responses; mice; mutant p53; p53-dependent apoptosis; p53-inducible regulator; restoration; senescence; tumorigenesis |
Datum der Freischaltung: | 25.02.2016 |
Lizenz (Deutsch): | CC BY-NC-ND: Creative-Commons-Lizenz: Namensnennung, Nicht kommerziell, Keine Bearbeitung |