Inhibition of p53 degradation by Mdm2 acetylation.
Mdm2 is a RING finger E3 ubiquitin ligase, which promotes ubiquitination and proteasomal degradation of the p53 tumor suppressor protein. Acetylation of p53 regulates p53's transcriptional activity and inhibits Mdm2-mediated p53 ubiquitination and degradation. We now report that Mdm2 is also a target for acetylation. Mdm2 is acetylated in vitro by CREB-binding protein (CBP) and to a lesser extent by p300, but not by p300/CPB-associated factor. Acetylation occurs primarily within the RING finger domain of Mdm2. In vivo acetylation of Mdm2 was detected easily with CBP but not p300. Efficient in vivo acetylation required the preservation of the RING finger. An Mdm2 mutant (K466/467Q) mimicking acetylation is impaired in its ability to promote p53 ubiquitination, as well as Mdm2 autoubiquitination. Moreover, K466/467Q is defective in promoting p53 degradation in living cells. We thus suggest that acetyltransferases may modulate cellular p53 activity not only by modifying p53, but also by inactivating Mdm2.
Wang
Xinjiang
X
Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot 76100, Israel.
Taplick
Jan
J
Geva
Naama
N
Oren
Moshe
M
D000107:Acetylation; D050882:CREB-Binding Protein; D002460:Cell Line; D004249:DNA Damage; D006801:Humans; D009154:Mutation; D009687:Nuclear Proteins / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2; D015534:Trans-Activators / Q000378:metabolism; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases
D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D025801:Ubiquitin; D050882:CREB-Binding Protein; C494363:CREBBP protein, human; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D044767:Ubiquitin-Protein Ligases