Regulation of p53 localization and transcription by the HECT domain E3 ligase WWP1.
As a key cellular regulatory protein p53 is subject to tight regulation by several E3 ligases. Here, we demonstrate the role of HECT domain E3 ligase, WWP1, in regulating p53 localization and activity. WWP1 associates with p53 and induces p53 ubiquitylation. Unlike other E3 ligases, WWP1 increases p53 stability; inhibition of WWP1 expression or expression of a ligase-mutant form results in decreased p53 expression. WWP1-mediated stabilization of p53 is associated with increased accumulation of p53 in cytoplasm with a concomitant decrease in its transcriptional activities. WWP1 effects are independent of Mdm2 as they are seen in cells lacking Mdm2 expression. Whereas WWP1 limits p53 activity, p53 reduces expression of WWP1, pointing to a possible feedback loop mechanism. Taken together, these findings identify the first instance of a ubiquitin ligase that causes stabilization of p53 while inactivating its transcriptional activities.
Laine
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Signal Transduction Program, The Burnham Institute for Medical Research, La Jolla, CA 92037, USA.
Ronai
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D020816:Amino Acid Motifs; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D003593:Cytoplasm / Q000378:metabolism; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000502:physiology*
D002352:Carrier Proteins; D005231:Fatty Acids, Unsaturated; D008565:Membrane Proteins; C451223:NDFIP1 protein, human; D016159:Tumor Suppressor Protein p53; D025801:Ubiquitin; C471642:WWP1 protein, human; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D044767:Ubiquitin-Protein Ligases; C038753:leptomycin B