Polyubiquitination of p53 by a ubiquitin ligase activity of p300.
Rapid turnover of the tumor suppressor protein p53 requires the MDM2 ubiquitin ligase, and both interact with p300-CREB-binding protein transcriptional coactivator proteins. p53 is stabilized by the binding of p300 to the oncoprotein E1A, suggesting that p300 regulates p53 degradation. Purified p300 exhibited intrinsic ubiquitin ligase activity that was inhibited by E1A. In vitro, p300 with MDM2 catalyzed p53 polyubiquitination, whereas MDM2 catalyzed p53 monoubiquitination. E1A expression caused a decrease in polyubiquitinated but not monoubiquitinated p53 in cells. Thus, generation of the polyubiquitinated forms of p53 that are targeted for proteasome degradation requires the intrinsic ubiquitin ligase activities of MDM2 and p300.
Grossman
Steven R
SR
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Deato
Maria E
ME
Brignone
Chrystelle
C
Chan
Ho Man
HM
Kung
Andrew L
AL
Tagami
Hideaki
H
Nakatani
Yoshihiro
Y
Livingston
David M
DM
D017500:Adenovirus E1A Proteins / Q000378:metabolism; D000818:Animals; D002384:Catalysis; D002478:Cells, Cultured; D050881:E1A-Associated p300 Protein; D004622:Embryo, Mammalian; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D008025:Ligases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases; D014452:Ubiquitins / Q000378:metabolism*
D017500:Adenovirus E1A Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D014452:Ubiquitins; D050881:E1A-Associated p300 Protein; C494361:Ep300 protein, mouse; C497206:MDM2 protein, human; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D044767:Ubiquitin-Protein Ligases; D008025:Ligases