title: Erbin is a novel substrate of the Sag-βTrCP E3 ligase that regulates KrasG12D-induced skin tumorigenesis.
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 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.
authors.affiliation: Division of Radiation and Cancer Biology, Department of Radiation Oncology, University of Michigan, Ann Arbor, MI 48109.
authors.forename: Chuan-Ming
authors.initials: CM
authors.lastname: Xie
authors.affiliation: Division of Radiation and Cancer Biology, Department of Radiation Oncology, University of Michigan, Ann Arbor, MI 48109.
authors.forename: Dongping
authors.initials: D
authors.lastname: Wei
authors.affiliation: Department of Biostatistics, University of Michigan, Ann Arbor, MI 48109.
authors.forename: Lili
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Cancer Research Center of Marseille, Cell Polarity, Cell Signalling and Cancer, Institut National de la Santé et de la Recherche Médicale U1068, 13009 Marseille, France Institut Paoli-Calmettes, 13009 Marseille, France Aix-Marseille Université, 13284 Marseille, France Centre National de la Recherche Scientifique UMR7258, 13009 Marseille, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Marchetto
authors.affiliation: Department of Neurology, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912 Department of Neuroscience and Regenerative Medicine, Georgia Regents University, Augusta, GA 30912.
authors.forename: Lin
authors.initials: L
authors.lastname: Mei
authors.affiliation: Cancer Research Center of Marseille, Cell Polarity, Cell Signalling and Cancer, Institut National de la Santé et de la Recherche Médicale U1068, 13009 Marseille, France Institut Paoli-Calmettes, 13009 Marseille, France Aix-Marseille Université, 13284 Marseille, France Centre National de la Recherche Scientifique UMR7258, 13009 Marseille, France.
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Borg
authors.affiliation: Division of Radiation and Cancer Biology, Department of Radiation Oncology, University of Michigan, Ann Arbor, MI 48109 Institute of Translational Medicine, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310058, Zhejiang, China Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou 310058, Zhejiang, China sunyi@umich.edu yisun@zju.edu.cn.
authors.forename: Yi
authors.initials: Y
authors.lastname: Sun
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D017353:Gene Deletion; D047908:Intracellular Signaling Peptides and Proteins; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000235:genetics; D051379:Mice; D020125:Mutation, Missense; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D010212:Papilloma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D044844:beta-Transducin Repeat-Containing Proteins / Q000235:genetics / Q000378:metabolism*; D048490:raf Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; C498804:Erbb2ip protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D017382:Reactive Oxygen Species; C573100:SAG protein, mouse; D044844:beta-Transducin Repeat-Containing Proteins; D044767:Ubiquitin-Protein Ligases; D048490:raf Kinases; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)