title: Inactivation of p53 in Human Keratinocytes Leads to Squamous Differentiation and Shedding via Replication Stress and Mitotic Slippage.
abstract: Tumor suppressor p53 is a major cellular guardian of genome integrity, and its inactivation is the most frequent genetic alteration in cancer, rising up to 80% in squamous cell carcinoma (SCC). By adapting the small hairpin RNA (shRNA) technology, we inactivated endogenous p53 in primary epithelial cells from the epidermis of human skin. We show that either loss of endogenous p53 or overexpression of a temperature-sensitive dominant-negative conformation triggers a self-protective differentiation response, resulting in cell stratification and expulsion. These effects follow DNA damage and exit from mitosis without cell division. p53 preserves the proliferative potential of the stem cell compartment and limits the power of proto-oncogene MYC to drive cell cycle stress and differentiation. The results provide insight into the role of p53 in self-renewal homeostasis and help explain why p53 mutations do not initiate skin cancer but increase the likelihood that cancer cells will appear.
authors.affiliation: Cell Cycle, Stem Cell Fate and Cancer Laboratory, Fundación Instituto de Investigación Marqués de Valdecilla (IDIVAL), Santander 39011, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Freije
authors.affiliation: Cell Cycle, Stem Cell Fate and Cancer Laboratory, Fundación Instituto de Investigación Marqués de Valdecilla (IDIVAL), Santander 39011, Spain.
authors.forename: Rut
authors.initials: R
authors.lastname: Molinuevo
authors.affiliation: Cell Cycle, Stem Cell Fate and Cancer Laboratory, Fundación Instituto de Investigación Marqués de Valdecilla (IDIVAL), Santander 39011, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Ceballos
authors.affiliation: Cell Cycle, Stem Cell Fate and Cancer Laboratory, Fundación Instituto de Investigación Marqués de Valdecilla (IDIVAL), Santander 39011, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Cagigas
authors.affiliation: Cell Cycle, Stem Cell Fate and Cancer Laboratory, Fundación Instituto de Investigación Marqués de Valdecilla (IDIVAL), Santander 39011, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Alonso-Lecue
authors.affiliation: Lab 2-ORL, Instituto Universitario de Oncología de Asturias (IUOPA) Hospital Universitario Central de Asturias (HUCA), Oviedo 33006, Spain.
authors.forename: René
authors.initials: R
authors.lastname: Rodriguez
authors.affiliation: Josep Carreras Leukaemia Research Institute, School of Medicine, University of Barcelona, Barcelona 08036, Spain; Instituciò Catalana de Recerca i Estudis Avançats (ICREA), Avenida Lluis Companys, Barcelona 08010, Spain.
authors.forename: Pablo
authors.initials: P
authors.lastname: Menendez
authors.affiliation: INSERM UMR-S976, University Paris Didero, Hôpital Saint-Louis, Equerre Bazin, Paris 75475, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Aberdam
authors.affiliation: Cell Cycle, Stem Cell Fate and Cancer Laboratory, Fundación Instituto de Investigación Marqués de Valdecilla (IDIVAL), Santander 39011, Spain; Paediatric Surgery, Hospital Universitario Marqués de Valdecilla (HUMV), Santander 39011, Spain.
authors.forename: Ernesto
authors.initials: E
authors.lastname: De Diego
authors.affiliation: Cell Cycle, Stem Cell Fate and Cancer Laboratory, Fundación Instituto de Investigación Marqués de Valdecilla (IDIVAL), Santander 39011, Spain; INSERM, Languedoc-Roussillon, Montpellier 34394, France. Electronic address: agandarillas@idival.org.
authors.forename: Alberto
authors.initials: A
authors.lastname: Gandarillas
mesh_terms: D000818:Animals; D002451:Cell Compartmentation; D002454:Cell Differentiation; D049109:Cell Proliferation; D002999:Clone Cells; D004249:DNA Damage; D004261:DNA Replication; D000078404:Epidermal Cells; D006801:Humans; D015603:Keratinocytes / Q000166:cytology* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008938:Mitosis; D008954:Models, Biological; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D013312:Stress, Physiological; D013696:Temperature; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: C000715470:MAS1 protein, human; D050505:Mutant Proteins; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc; D016159:Tumor Suppressor Protein p53