Acetylation of p53 inhibits its ubiquitination by Mdm2.
In response to DNA damage, the activity of the p53 tumor suppressor is modulated by protein stabilization and post-translational modifications including acetylation. Interestingly, both acetylation and ubiquitination can modify the same lysine residues at the C terminus of p53, implicating a role of acetylation in the regulation of p53 stability. However, the direct effect of acetylation on Mdm2-mediated ubiquitination of p53 is still lacking because of technical difficulties. Here, we have developed a method to obtain pure acetylated p53 proteins from cells, and by using an in vitro purified system, we provide the direct evidence that acetylation of the C-terminal domain is sufficient to abrogate its ubiquitination by Mdm2. Importantly, even in the absence of DNA damage, acetylation of the p53 protein is capable of reducing the ubiquitination levels and extending its half-life in vivo. Moreover, we also show that acetylation of p53 can affect its ubiquitination through other mechanisms in addition to the site competition. This study has significant implications regarding a general mechanism by which protein acetylation modulates ubiquitination-dependent proteasome proteolysis.
Li
Muyang
M
Institute for Cancer Genetics, and Department of Pathology, College of Physicians & Surgeons, Columbia University, New York, New York 10032, USA.
Luo
Jianyuan
J
Brooks
Christopher L
CL
Gu
Wei
W
D000107:Acetylation; D000818:Animals; D002051:Burkitt Lymphoma; D003001:Cloning, Molecular; D004249:DNA Damage; D006367:HeLa Cells; D006801:Humans; D007700:Kinetics; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D009687:Nuclear Proteins; D011499:Protein Processing, Post-Translational; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2; D011994:Recombinant Proteins / Q000378:metabolism; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism*
D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins; D016159:Tumor Suppressor Protein p53; D025801:Ubiquitin; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2