title: ΔNp63α is an oncogene that targets chromatin remodeler Lsh to drive skin stem cell proliferation and tumorigenesis.
abstract: The p53 homolog p63 is essential for development, yet its role in cancer is not clear. We discovered that p63 deficiency evokes the tumor-suppressive mechanism of cellular senescence, causing a striking absence of stratified epithelia such as the skin. Here we identify the predominant p63 isoform, ΔNp63α, as a protein that bypasses oncogene-induced senescence to drive tumorigenesis in vivo. Interestingly, bypass of senescence promotes stem-like proliferation and maintains survival of the keratin 15-positive stem cell population. Furthermore, we identify the chromatin-remodeling protein Lsh as a new target of ΔNp63α that is an essential mediator of senescence bypass. These findings indicate that ΔNp63α is an oncogene that cooperates with Ras to promote tumor-initiating stem-like proliferation and suggest that Lsh-mediated chromatin-remodeling events are critical to this process.
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA. bill.keyes@crg.es
authors.forename: William M
authors.initials: WM
authors.lastname: Keyes
authors.forename: Matteo
authors.initials: M
authors.lastname: Pecoraro
authors.forename: Victoria
authors.initials: V
authors.lastname: Aranda
authors.forename: Emma
authors.initials: E
authors.lastname: Vernersson-Lindahl
authors.forename: Wangzhi
authors.initials: W
authors.lastname: Li
authors.forename: Hannes
authors.initials: H
authors.lastname: Vogel
authors.forename: Xuecui
authors.initials: X
authors.lastname: Guo
authors.forename: Elvin L
authors.initials: EL
authors.lastname: Garcia
authors.forename: Tatyana V
authors.initials: TV
authors.lastname: Michurina
authors.forename: Grigori
authors.initials: G
authors.lastname: Enikolopov
authors.forename: Senthil K
authors.initials: SK
authors.lastname: Muthuswamy
authors.forename: Alea A
authors.initials: AA
authors.lastname: Mills
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D004265:DNA Helicases / Q000378:metabolism*; D005434:Flow Cytometry; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D011485:Protein Binding; D012867:Skin / Q000166:cytology*; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*
chemical_list: D010750:Phosphoproteins; D015534:Trans-Activators; C486419:Trp63 protein, mouse; D004265:DNA Helicases; C412063:HELLS protein, human