TY - JOUR
T1 - Erbin is a novel substrate of the Sag-βTrCP E3 ligase that regulates KrasG12D-induced skin tumorigenesis
AU - Xie, Chuan Ming
AU - Wei, Dongping
AU - Zhao, Lili
AU - Marchetto, Sylvie
AU - Mei, Lin
AU - Borg, Jean Paul
AU - Sun, Yi
N1 - Funding Information:
This work was supported by National Cancer Institute grants (CA118762, CA156744, and CA171277) to Y. Sun and by La Ligue Contre le Cancer (Label Ligue) and Institut Paoli-Calmettes grants to J.-P. Borg. J.-P.Borg is a member of Institut Universitaire de France.
Publisher Copyright:
© 2015 Xie et al.
PY - 2015
Y1 - 2015
N2 - 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.
AB - 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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U2 - 10.1083/jcb.201411104
DO - 10.1083/jcb.201411104
M3 - Article
C2 - 26056141
AN - SCOPUS:84957793911
SN - 0021-9525
VL - 209
SP - 721
EP - 738
JO - Journal of Cell Biology
JF - Journal of Cell Biology
IS - 5
ER -