title: Transcription factor Etv5 is essential for the maintenance of alveolar type II cells.
abstract: Alveolar type II (AT2) cell dysfunction contributes to a number of significant human pathologies including respiratory distress syndrome, lung adenocarcinoma, and debilitating fibrotic diseases, but the critical transcription factors that maintain AT2 cell identity are unknown. Here we show that the E26 transformation-specific (ETS) family transcription factor Etv5 is essential to maintain AT2 cell identity. Deletion ofEtv5from AT2 cells produced gene and protein signatures characteristic of differentiated alveolar type I (AT1) cells. Consistent with a defect in the AT2 stem cell population,Etv5deficiency markedly reduced recovery following bleomycin-induced lung injury. Lung tumorigenesis driven by mutant KrasG12D was also compromised by Etv5 deficiency. ERK activation downstream of Ras was found to stabilize Etv5 through inactivation of the cullin-RING ubiquitin ligase CRL4COP1/DET1that targets Etv5 for proteasomal degradation. These findings identify Etv5 as a critical output of Ras signaling in AT2 cells, contributing to both lung homeostasis and tumor initiation.
authors.affiliation: Department of Physiological Chemistry, Genentech, South San Francisco, CA 94080.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Physiological Chemistry, Genentech, South San Francisco, CA 94080.
authors.forename: Kim
authors.initials: K
authors.lastname: Newton
authors.affiliation: Department of Bioinformatics and Computational Biology, Genentech, South San Francisco, CA 94080.
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Kummerfeld
authors.affiliation: Department of Pathology, Genentech, South San Francisco, CA 94080.
authors.forename: Joshua
authors.initials: J
authors.lastname: Webster
authors.affiliation: Department of Protein Chemistry, Genentech, South San Francisco, CA 94080.
authors.forename: Donald S
authors.initials: DS
authors.lastname: Kirkpatrick
authors.affiliation: Department of Protein Chemistry, Genentech, South San Francisco, CA 94080.
authors.forename: Lilian
authors.initials: L
authors.lastname: Phu
authors.affiliation: Department of Pathology, Genentech, South San Francisco, CA 94080.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Eastham-Anderson
authors.affiliation: Department of Bioinformatics and Computational Biology, Genentech, South San Francisco, CA 94080.
authors.forename: Jinfeng
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Translational Immunology, Genentech, South San Francisco, CA 94080.
authors.forename: Wyne P
authors.initials: WP
authors.lastname: Lee
authors.affiliation: Department of Protein Chemistry, Genentech, South San Francisco, CA 94080.
authors.forename: Jiansheng
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Protein Chemistry, Genentech, South San Francisco, CA 94080.
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Translational Oncology, Genentech, South San Francisco, CA 94080.
authors.forename: Melissa R
authors.initials: MR
authors.lastname: Junttila
authors.affiliation: Department of Physiological Chemistry, Genentech, South San Francisco, CA 94080; dixit@gene.com.
authors.forename: Vishva M
authors.initials: VM
authors.lastname: Dixit
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects; D001761:Bleomycin; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D008175:Lung Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000473:pathology*; D008817:Mice, Mutant Strains; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D055550:Protein Stability; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D011650:Pulmonary Alveoli / Q000166:cytology* / Q000187:drug effects / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D004268:DNA-Binding Proteins; C513242:Etv5 protein, mouse; D009687:Nuclear Proteins; D014157:Transcription Factors; D001761:Bleomycin; C471982:COP1 protein, mouse; D044767:Ubiquitin-Protein Ligases; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)
keywords: Cop1; Etv5; Ras; lung cancer