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.
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.
Stavridi
E S
ES
The Wistar Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104-4268, USA.
Chehab
N H
NH
Malikzay
A
A
Halazonetis
T D
TD
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*
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