Abstract
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.
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Acknowledgements
We thank Marius Sudol and Tony Hunter for providing us with WWP1 reagents, Stephen Jones for p53/Mdm2 DKO cells, and ZQ Pan, J Manfredi and M O'Connell for advice. A Laine performed these studies as part of his work for the MD/PhD program at Mount Sinai School of Medicine, New York, NY. Support by NCI grant CA78419 to ZR is gratefully acknowledged.
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Laine, A., Ronai, Z. Regulation of p53 localization and transcription by the HECT domain E3 ligase WWP1. Oncogene 26, 1477–1483 (2007). https://doi.org/10.1038/sj.onc.1209924
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DOI: https://doi.org/10.1038/sj.onc.1209924
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