Mechanism of p53 stabilization by ATM after DNA damage.
p53 suppresses tumor development by responding to unauthorized cell proliferation, growth factor or nutrient deprivation, and DNA damage. Distinct pathways have been identified that cause p53 activation, including ARF-dependent response to oncogene activation, ribosomal protein-mediated response to abnormal rRNA synthesis, and ATM-dependent response to DNA damage. Elucidating the mechanisms of these signaling events are critical for understanding tumor suppression by p53 and development of novel cancer therapeutics. More than a decade of research has established the ATM kinase as a key molecule that activates p53 after DNA damage. Our recent study revealed that ATM phosphorylation of MDM2 is likely to be the key step in causing p53 stabilization. Upon activation by ionizing irradiation, ATM phosphorylates MDM2 on multiple sites near its RING domain. These modifications inhibit the ability of MDM2 to poly-ubiquitinate p53, thus leading to its stabilization. MDM2 phosphorylation does not inactivate its E3 ligase activity per se, since MDM2 self-ubiquitination and MDMX ubiquitination functions are retained. The selective inhibition of p53 poly-ubiquitination is accomplished through disrupting MDM2 oligomerization that may provide a scaffold for processive elongation of poly ubiquitin chains. These findings suggest a novel model of p53 activation and a general mechanism of E3 ligase regulation by phosphorylation.
Cheng
Qian
Q
Molecular Oncology Department, Mofftt Cancer Center, Tampa, FL, USA.
Chen
Jiandong
J
D000595:Amino Acid Sequence; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism*; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D008969:Molecular Sequence Data; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D055550:Protein Stability; D020836:Protein Structure, Quaternary; D051736:Proto-Oncogene Proteins c-mdm2 / Q000737:chemistry / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D051736:Proto-Oncogene Proteins c-mdm2; D044767:Ubiquitin-Protein Ligases; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases