title: p21 suppresses inflammation and tumorigenesis on pRB-deficient stratified epithelia.
abstract: The retinoblastoma gene product (pRb) controls proliferation and differentiation processes in stratified epithelia. Importantly, and in contrast to other tissues, Rb deficiency does not lead to spontaneous skin tumor formation. As the cyclin-dependent kinase inhibitor p21 regulates proliferation and differentiation in the absence of pRb, we analyzed the consequences of deleting p21 in pRb-ablated stratified epithelia (hereafter pRb(ΔEpi);p21-/-). These mice display an enhancement of the phenotypic abnormalities observed in pRb(ΔEpi) animals, indicating that p21 partially compensates pRb absence. Remarkably, pRb(ΔEpi);p21-/- mice show an acute skin inflammatory phenotype and develop spontaneous epithelial tumors, particularly affecting tongue and oral tissues. Biochemical analyses and transcriptome studies reveal changes affecting multiple pathways, including DNA damage and p53-dependent signaling responses. Comparative metagenomic analyses, together with the histopathological profiles, indicate that these mice constitute a faithful model for human head and neck squamous cell carcinomas. Collectively, our findings demonstrate that p21, in conjunction with pRb, has a central role in regulating multiple epithelial processes and orchestrating specific tumor suppressor functions.
authors.affiliation: Molecular Oncology Unit. Division of Biomedicine, CIEMAT (ed70A). Ave. Complutense 40, E-28040 Madrid, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Saiz-Ladera
authors.affiliation: Molecular Oncology Unit. Division of Biomedicine, CIEMAT (ed70A). Ave. Complutense 40, E-28040 Madrid, Spain.
authors.forename: María Fernanda
authors.initials: MF
authors.lastname: Lara
authors.affiliation: Division of Hematopoietic Innovative Therapies (HIT). Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT)/Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBER-ER). Madrid, Spain.
authors.forename: Marina
authors.initials: M
authors.lastname: Garín
authors.affiliation: Genomic Instability Group, Spanish National Cancer Research Center, Madrid, Spain.
authors.forename: Sergio
authors.initials: S
authors.lastname: Ruiz
authors.affiliation: Molecular Oncology Unit. Division of Biomedicine, CIEMAT (ed70A). Ave. Complutense 40, E-28040 Madrid, Spain.
authors.forename: Mirentxu
authors.initials: M
authors.lastname: Santos
authors.affiliation: Molecular Oncology Unit. Division of Biomedicine, CIEMAT (ed70A). Ave. Complutense 40, E-28040 Madrid, Spain.
authors.forename: Corina
authors.initials: C
authors.lastname: Lorz
authors.affiliation: Molecular Oncology Unit. Division of Biomedicine, CIEMAT (ed70A). Ave. Complutense 40, E-28040 Madrid, Spain.
authors.forename: Ramón
authors.initials: R
authors.lastname: García-Escudero
authors.affiliation: Molecular Oncology Unit. Division of Biomedicine, CIEMAT (ed70A). Ave. Complutense 40, E-28040 Madrid, Spain.
authors.forename: Mónica
authors.initials: M
authors.lastname: Martínez-Fernández
authors.affiliation: Department of Veterinary Clinical Sciences Veterinary Faculty, University of Santiago de Compostela, E-27002 Lugo, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Bravo
authors.affiliation: Genomic Instability Group, Spanish National Cancer Research Center, Madrid, Spain.
authors.forename: Oscar
authors.initials: O
authors.lastname: Fernández-Capetillo
authors.affiliation: Molecular Oncology Unit. Division of Biomedicine, CIEMAT (ed70A). Ave. Complutense 40, E-28040 Madrid, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Segrelles
authors.affiliation: Molecular Oncology Unit. Division of Biomedicine, CIEMAT (ed70A). Ave. Complutense 40, E-28040 Madrid, Spain.
authors.forename: Jesús M
authors.initials: JM
authors.lastname: Paramio
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000378:metabolism; D049109:Cell Proliferation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D004249:DNA Damage; D004848:Epithelium / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006258:Head and Neck Neoplasms / Q000378:metabolism; D006801:Humans; D007249:Inflammation; D015603:Keratinocytes / Q000166:cytology; D051379:Mice; D016513:Mice, SCID; D010641:Phenotype; D016160:Retinoblastoma Protein / Q000378:metabolism*; D015398:Signal Transduction; D012867:Skin / Q000473:pathology; D059467:Transcriptome; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53