biostudies-literatureOkamoto KNCPDCID CDC HHSNINDS NIH HHS9608-20https://www.ebi.ac.uk/biostudies/studies/S-EPMC1265801biostudies-literatureUnknown25(21)Understanding how p53 activity is regulated is crucial in elucidating mechanisms of cellular defense against cancer. Genetic data indicate that Mdmx as well as Mdm2 plays a major role in maintaining p53 activity at low levels in nonstressed cells. However, biochemical mechanisms of how Mdmx regulates p53 activity are not well understood. Through identification of Mdmx-binding proteins, we found that 14-3-3 proteins are associated with Mdmx. Mdmx harbors a consensus sequence for binding of 14-3-3. Serine 367 (S367) is located within the putative binding sequence for 14-3-3, and its substitution with alanine (S367A) abolishes binding of Mdmx to 14-3-3. Transfection assays indicated that the S367A mutation, in cooperation with Mdm2, enhances the ability of Mdmx to repress the transcriptional Molecular and cellular biologyDNA damage-induced phosphorylation of MdmX at serine 367 activates p53 by targeting MdmX for Mdm2-dependent degradation.PMC1265801NS 31763R01 NS031763NCI 87497Kashima KTeunisse AMarine JCNota AIshida MOkamoto KMigliorini DJochemsen AGTaya YShiloh YPereg YKitabayashi IYamazaki SPrives CfalseDNA damage-induced phosphorylation of MdmX at serine 367 activates p53 by targeting MdmX for Mdm2-dependent degradation.Understanding how p53 activity is regulated is crucial in elucidating mechanisms of cellular defense against cancer. Genetic data indicate that Mdmx as well as Mdm2 plays a major role in maintaining p53 activity at low levels in nonstressed cells. However, biochemical mechanisms of how Mdmx regulates p53 activity are not well understood. Through identification of Mdmx-binding proteins, we found that 14-3-3 proteins are associated with Mdmx. Mdmx harbors a consensus sequence for binding of 14-3-3. Serine 367 (S367) is located within the putative binding sequence for 14-3-3, and its substitution with alanine (S367A) abolishes binding of Mdmx to 14-3-3. Transfection assays indicated that the S367A mutation, in cooperation with Mdm2, enhances the ability of Mdmx to repress the transcriptional 2005-01-01T00:00:00Z2005 Nov2025-04-18T16:09:35.155Z2019-03-27T01:25:22ZS-EPMC12658011622760910.1128/MCB.25.21.9608-9620.200510.1128/mcb.25.21.9608-9620.2005