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MDM2 Inhibits Axin-Induced p53 Activation Independently of its E3 Ligase Activity

MDM2 plays a crucial role in negatively regulating the functions of tumor suppressor p53. Here we show that MDM2 can inhibit Axin-stimulated p53-dependent apoptosis by suppressing p53 phosphorylation at Ser 46 and apoptosis-related p53 transactivational activity. Interestingly, the ubiquitin E3 liga...

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Autores principales: He, Ying, Lian, Guili, Lin, Shuyong, Ye, Zhiyun, Li, Qinxi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3694902/
https://www.ncbi.nlm.nih.gov/pubmed/23826318
http://dx.doi.org/10.1371/journal.pone.0067529
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author He, Ying
Lian, Guili
Lin, Shuyong
Ye, Zhiyun
Li, Qinxi
author_facet He, Ying
Lian, Guili
Lin, Shuyong
Ye, Zhiyun
Li, Qinxi
author_sort He, Ying
collection PubMed
description MDM2 plays a crucial role in negatively regulating the functions of tumor suppressor p53. Here we show that MDM2 can inhibit Axin-stimulated p53-dependent apoptosis by suppressing p53 phosphorylation at Ser 46 and apoptosis-related p53 transactivational activity. Interestingly, the ubiquitin E3 ligase activity of MDM2 is not required for this inhibitory effect. Mechanically, either wildtype MDM2 or its E3-dead mutant, disrupts the Axin-based HIPK2/p53 complex formation by blocking the binding of p53 and HIPK2 to Axin. MDM2Δp53, a deletion mutant that lacks p53 binding domain fails to exert the inhibitory effect, demonstrating that the interaction of MDM2 and p53, but not its E3 ligase activity toward p53 plays key role in suppressing Axin-stimulated p53 activation. Our results thus have revealed a novel aspect of the mechanism by which MDM2 regulates p53 activities.
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spelling pubmed-36949022013-07-03 MDM2 Inhibits Axin-Induced p53 Activation Independently of its E3 Ligase Activity He, Ying Lian, Guili Lin, Shuyong Ye, Zhiyun Li, Qinxi PLoS One Research Article MDM2 plays a crucial role in negatively regulating the functions of tumor suppressor p53. Here we show that MDM2 can inhibit Axin-stimulated p53-dependent apoptosis by suppressing p53 phosphorylation at Ser 46 and apoptosis-related p53 transactivational activity. Interestingly, the ubiquitin E3 ligase activity of MDM2 is not required for this inhibitory effect. Mechanically, either wildtype MDM2 or its E3-dead mutant, disrupts the Axin-based HIPK2/p53 complex formation by blocking the binding of p53 and HIPK2 to Axin. MDM2Δp53, a deletion mutant that lacks p53 binding domain fails to exert the inhibitory effect, demonstrating that the interaction of MDM2 and p53, but not its E3 ligase activity toward p53 plays key role in suppressing Axin-stimulated p53 activation. Our results thus have revealed a novel aspect of the mechanism by which MDM2 regulates p53 activities. Public Library of Science 2013-06-27 /pmc/articles/PMC3694902/ /pubmed/23826318 http://dx.doi.org/10.1371/journal.pone.0067529 Text en © 2013 He et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
He, Ying
Lian, Guili
Lin, Shuyong
Ye, Zhiyun
Li, Qinxi
MDM2 Inhibits Axin-Induced p53 Activation Independently of its E3 Ligase Activity
title MDM2 Inhibits Axin-Induced p53 Activation Independently of its E3 Ligase Activity
title_full MDM2 Inhibits Axin-Induced p53 Activation Independently of its E3 Ligase Activity
title_fullStr MDM2 Inhibits Axin-Induced p53 Activation Independently of its E3 Ligase Activity
title_full_unstemmed MDM2 Inhibits Axin-Induced p53 Activation Independently of its E3 Ligase Activity
title_short MDM2 Inhibits Axin-Induced p53 Activation Independently of its E3 Ligase Activity
title_sort mdm2 inhibits axin-induced p53 activation independently of its e3 ligase activity
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3694902/
https://www.ncbi.nlm.nih.gov/pubmed/23826318
http://dx.doi.org/10.1371/journal.pone.0067529
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