Erbin is a novel substrate of the Sag-βTrCP E3 ligase that regulates KrasG12D-induced skin tumorigenesis

Chuan Ming Xie, Dongping Wei, Lili Zhao, Sylvie Marchetto, Lin Mei, Jean Paul Borg, Yi Sun

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

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 KrasG12D-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 KrasG12D-induced papillomagenesis. In KrasG12D-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 KrasG12D-induced papillomagenesis and thus acting as a skin-specific tumor suppressor.

Original languageEnglish (US)
Pages (from-to)721-738
Number of pages18
JournalJournal of Cell Biology
Volume209
Issue number5
DOIs
StatePublished - Jan 1 2015

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Ubiquitin-Protein Ligases
Reactive Oxygen Species
Carcinogenesis
Autophagy
Skin
Cullin Proteins
Gene Components
Sirolimus
Ligases
Keratinocytes
Genes
Alleles
Phenotype
Lung
Neoplasms

ASJC Scopus subject areas

  • Cell Biology

Cite this

Erbin is a novel substrate of the Sag-βTrCP E3 ligase that regulates KrasG12D-induced skin tumorigenesis. / Xie, Chuan Ming; Wei, Dongping; Zhao, Lili; Marchetto, Sylvie; Mei, Lin; Borg, Jean Paul; Sun, Yi.

In: Journal of Cell Biology, Vol. 209, No. 5, 01.01.2015, p. 721-738.

Research output: Contribution to journalArticle

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 KrasG12D-induced skin tumorigenesis. In: Journal of Cell Biology. 2015 ; Vol. 209, No. 5. pp. 721-738.
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abstract = "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 KrasG12D-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 KrasG12D-induced papillomagenesis. In KrasG12D-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 KrasG12D-induced papillomagenesis and thus acting as a skin-specific tumor suppressor.",
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