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Erbin is a novel substrate of the Sag-βTrCP E3 ligase that regulates Kras(G12D)-induced skin tumorigenesis

SAG/RBX2 is the RING (really interesting new gene) component of Cullin-RING ligase, which is required for its activity. An organ-specific role of SAG in tumorigenesis is unknown. We recently showed that Sag/Rbx2, upon lung-targeted deletion, suppressed Kras(G12D)-induced tumorigenesis via inactivati...

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Autores principales: Xie, Chuan-Ming, Wei, Dongping, Zhao, Lili, Marchetto, Sylvie, Mei, Lin, Borg, Jean-Paul, Sun, Yi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4460146/
https://www.ncbi.nlm.nih.gov/pubmed/26056141
http://dx.doi.org/10.1083/jcb.201411104
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author Xie, Chuan-Ming
Wei, Dongping
Zhao, Lili
Marchetto, Sylvie
Mei, Lin
Borg, Jean-Paul
Sun, Yi
author_facet Xie, Chuan-Ming
Wei, Dongping
Zhao, Lili
Marchetto, Sylvie
Mei, Lin
Borg, Jean-Paul
Sun, Yi
author_sort Xie, Chuan-Ming
collection PubMed
description SAG/RBX2 is the RING (really interesting new gene) component of Cullin-RING ligase, which is required for its activity. An organ-specific role of SAG in tumorigenesis is unknown. We recently showed that Sag/Rbx2, upon lung-targeted deletion, suppressed Kras(G12D)-induced tumorigenesis via inactivating NF-κB and mammalian target of rapamycin pathways. In contrast, we report here that, upon skin-targeted deletion, Sag significantly accelerated Kras(G12D)-induced papillomagenesis. In Kras(G12D)-expressing primary keratinocytes, Sag deletion promotes proliferation by inhibiting autophagy and senescence, by inactivating the Ras–Erk pathway, and by blocking reactive oxygen species (ROS) generation. This is achieved by accumulation of Erbin to block Ras activation of Raf and Nrf2 to scavenge ROS and can be rescued by knockdown of Nrf2 or Erbin. Simultaneous one-allele deletion of the Erbin-encoding gene Erbb2ip partially rescued the phenotypes. Finally, we characterized Erbin as a novel substrate of SAG-βTrCP E3 ligase. By degrading Erbin and Nrf2, Sag activates the Ras–Raf pathway and causes ROS accumulation to trigger autophagy and senescence, eventually delaying Kras(G12D)-induced papillomagenesis and thus acting as a skin-specific tumor suppressor.
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spelling pubmed-44601462015-12-08 Erbin is a novel substrate of the Sag-βTrCP E3 ligase that regulates Kras(G12D)-induced skin tumorigenesis Xie, Chuan-Ming Wei, Dongping Zhao, Lili Marchetto, Sylvie Mei, Lin Borg, Jean-Paul Sun, Yi J Cell Biol Research Articles SAG/RBX2 is the RING (really interesting new gene) component of Cullin-RING ligase, which is required for its activity. An organ-specific role of SAG in tumorigenesis is unknown. We recently showed that Sag/Rbx2, upon lung-targeted deletion, suppressed Kras(G12D)-induced tumorigenesis via inactivating NF-κB and mammalian target of rapamycin pathways. In contrast, we report here that, upon skin-targeted deletion, Sag significantly accelerated Kras(G12D)-induced papillomagenesis. In Kras(G12D)-expressing primary keratinocytes, Sag deletion promotes proliferation by inhibiting autophagy and senescence, by inactivating the Ras–Erk pathway, and by blocking reactive oxygen species (ROS) generation. This is achieved by accumulation of Erbin to block Ras activation of Raf and Nrf2 to scavenge ROS and can be rescued by knockdown of Nrf2 or Erbin. Simultaneous one-allele deletion of the Erbin-encoding gene Erbb2ip partially rescued the phenotypes. Finally, we characterized Erbin as a novel substrate of SAG-βTrCP E3 ligase. By degrading Erbin and Nrf2, Sag activates the Ras–Raf pathway and causes ROS accumulation to trigger autophagy and senescence, eventually delaying Kras(G12D)-induced papillomagenesis and thus acting as a skin-specific tumor suppressor. The Rockefeller University Press 2015-06-08 /pmc/articles/PMC4460146/ /pubmed/26056141 http://dx.doi.org/10.1083/jcb.201411104 Text en © 2015 Xie et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
spellingShingle Research Articles
Xie, Chuan-Ming
Wei, Dongping
Zhao, Lili
Marchetto, Sylvie
Mei, Lin
Borg, Jean-Paul
Sun, Yi
Erbin is a novel substrate of the Sag-βTrCP E3 ligase that regulates Kras(G12D)-induced skin tumorigenesis
title Erbin is a novel substrate of the Sag-βTrCP E3 ligase that regulates Kras(G12D)-induced skin tumorigenesis
title_full Erbin is a novel substrate of the Sag-βTrCP E3 ligase that regulates Kras(G12D)-induced skin tumorigenesis
title_fullStr Erbin is a novel substrate of the Sag-βTrCP E3 ligase that regulates Kras(G12D)-induced skin tumorigenesis
title_full_unstemmed Erbin is a novel substrate of the Sag-βTrCP E3 ligase that regulates Kras(G12D)-induced skin tumorigenesis
title_short Erbin is a novel substrate of the Sag-βTrCP E3 ligase that regulates Kras(G12D)-induced skin tumorigenesis
title_sort erbin is a novel substrate of the sag-βtrcp e3 ligase that regulates kras(g12d)-induced skin tumorigenesis
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4460146/
https://www.ncbi.nlm.nih.gov/pubmed/26056141
http://dx.doi.org/10.1083/jcb.201411104
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