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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 Arrest¹

The Wistar Institute [E. S. S., N. H. C., A. M., T. D. H.], Program in Biochemistry [N. H. C.], and Department of Pathology and Laboratory Medicine [T. D. H.], University of Pennsylvania, Philadelphia, Pennsylvania 19104-4268

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 Ser³⁷⁶, 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 G₁ arrest was compromised, suggesting that the dephosphorylation of Ser³⁷⁶ and the association of p53 with 14-3-3 proteins contribute to the activation of p53 in response to IR.

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