The p53 tumor suppressor plays a major role in maintaining genomic stability. Its activation and stabilization in response to double strand breaks (DSBs) in DNA are regulated primarily by the ATM protein kinase. ATM mediates several posttranslational modifications on p53 itself, as well as phosphorylation of p53's essential inhibitors, Hdm2 and Hdmx. Recently we showed that ATM- and Hdm2-dependent ubiquitination and subsequent degradation of Hdmx following DSB induction are mediated by phosphorylation of Hdmx on S403, S367, and S342, with S403 being targeted directly by ATM. Here we show that S367 phosphorylation is mediated by the Chk2 protein kinase, a downstream kinase of ATM. This phosphorylation, which is important for subsequent Hdmx ubiquitination and degradation, creates a binding site for 14-3-3 proteins which controls nuclear accumulation of Hdmx following DSBs. Phosphorylation of S342 also contributed to optimal 14-3-3 interaction and nuclear accumulation of Hdmx, but phosphorylation of S403 did not. Our data indicate that binding of a 14-3-3 dimer and subsequent nuclear accumulation are essential steps toward degradation of p53's inhibitor, Hdmx, in response to DNA damage. These results demonstrate a sophisticated control by ATM of a target protein, Hdmx, which itself is one of several ATM targets in the ATM-p53 axis of the DNA damage response.
|Titolo:||Differential roles of ATM- and Chk2-mediated phosphorylations of Hdmx in response to DNA damage|
|Parole Chiave:||14-3-3 Proteins; Animals ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins ; Cell Nucleus ; Cells, Cultured ; Checkpoint Kinase 2 ; DNA Damage ; DNA-Binding Proteins ; Humans ; Mice ; Models, Biological ; Nuclear Proteins ; Phosphorylation ; Phosphoserine ; Protein Binding ; Protein Processing, Post-Translational ; Protein-Serine-Threonine Kinases ; Proto-Oncogene Proteins ; Tumor Suppressor Proteins|
|Settore Scientifico Disciplinare:||Settore BIO/11 - Biologia Molecolare|
|Data di pubblicazione:||2006|
|Digital Object Identifier (DOI):||10.1128/MCB.00562-06|
|Appare nelle tipologie:||01 - Articolo su periodico|