title: Substitutions that compromise the ionizing radiation-induced association of p53 with 14-3-3 proteins also compromise the ability of p53 to induce cell cycle arrest.
abstract: Ionizing radiation (IR) induces an increase in the levels and activity of the p53 tumor suppressor protein. The increased activity is attributed to IR-induced posttranslational modifications, some of which regulate the interaction of p53 with other proteins. One of these modifications is dephosphorylation of Ser(376), which leads to association of p53 with 14-3-3 proteins. To establish the significance of this interaction, we examined the function of mutant p53 proteins that do not interact with 14-3-3 proteins in vivo. These p53 mutants retained sequence-specific DNA binding activity. However, their ability to activate transcription of the endogenous p21/waf1/cip1 gene and to induce G(1) arrest was compromised, suggesting that the dephosphorylation of Ser(376) and the association of p53 with 14-3-3 proteins contribute to the activation of p53 in response to IR.
authors.affiliation: The Wistar Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104-4268, USA.
authors.forename: E S
authors.initials: ES
authors.lastname: Stavridi
authors.forename: N H
authors.initials: NH
authors.lastname: Chehab
authors.forename: A
authors.initials: A
authors.lastname: Malikzay
authors.forename: T D
authors.initials: TD
authors.lastname: Halazonetis
mesh_terms: D048948:14-3-3 Proteins; D002453:Cell Cycle / Q000502:physiology* / Q000528:radiation effects; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009154:Mutation; D012516:Osteosarcoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011233:Precipitin Tests; D020033:Protein Isoforms; D013379:Substrate Specificity; D015533:Transcriptional Activation / Q000502:physiology / Q000528:radiation effects; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism*
chemical_list: D048948:14-3-3 Proteins; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D020033:Protein Isoforms; D016159:Tumor Suppressor Protein p53; D014446:Tyrosine 3-Monooxygenase