title: Epiprofin orchestrates epidermal keratinocyte proliferation and differentiation.
abstract: The basal layer of the epidermis contains stem cells and transit amplifying cells that rapidly proliferate and differentiate further into the upper layers of the epidermis. A number of molecules have been identified as regulators of this process, including p63 (also known as tumor protein 63) and Notch1. However, little is known about the mechanisms that regulate the transitions from stem cell to proliferating or differentiating transit amplifying cell. Here, we demonstrate that epiprofin (Epfn, also known as Sp6) plays crucial distinct roles in these transition stages as a cell cycle regulator and a transcription factor. Epfn knockout mice have a thickened epidermis, in which p63-expressing basal cells form multiple layers owing to the accumulation of premature transit amplifying cells with reduced proliferation and a reduction in the number of differentiating keratinocytes expressing Notch1. We found that low levels of Epfn expression increased the proliferation of human immortalized keratinocyte (HaCaT) cells by increasing EGF responsiveness and superphosphorylation of Rb. By contrast, high levels of Epfn expression promoted cell cycle exit and differentiation, by reducing E2F transactivation and inducing Notch1 expression. Our findings identify multiple novel functions of Epfn in epidermal development.
authors.affiliation: Division of Pediatric Dentistry, Department of Oral Health and Development Sciences, Tohoku University Graduate School of Dentistry, Sendai 980-8575, Japan Liaison Center for Innovative Dentistry, Tohoku University Graduate School of Dentistry, Sendai 980-8575, Japan Laboratory of Cell and Developmental Biology, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA taka@dent.tohoku.ac.jp yoshi.yamada@nih.gov.
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakamura
authors.affiliation: Laboratory of Cell and Developmental Biology, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Yoshitomi
authors.affiliation: Laboratory of Cell and Developmental Biology, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Sakai
authors.affiliation: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Vyomesh
authors.initials: V
authors.lastname: Patel
authors.affiliation: Division of Pediatric Dentistry, Department of Oral Health and Development Sciences, Tohoku University Graduate School of Dentistry, Sendai 980-8575, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Fukumoto
authors.affiliation: Laboratory of Cell and Developmental Biology, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA taka@dent.tohoku.ac.jp yoshi.yamada@nih.gov.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Yamada
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000494:pharmacology; D004817:Epidermis / Q000254:growth & development / Q000473:pathology*; D018859:Hair Follicle / Q000254:growth & development / Q000473:pathology; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D051741:Kruppel-Like Transcription Factors / Q000172:deficiency / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D009024:Morphogenesis / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D051880:Receptors, Notch / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D051703:Sp Transcription Factors / Q000378:metabolism*
chemical_list: C417549:KLF14 protein, human; D051741:Kruppel-Like Transcription Factors; D051880:Receptors, Notch; D016160:Retinoblastoma Protein; D051703:Sp Transcription Factors; C498818:Sp6 protein, mouse; D004815:Epidermal Growth Factor; D051358:Cyclin-Dependent Kinase 4
keywords: Differentiation; Keratinocyte; Notch; Proliferation; Skin development; Sp transcription factor; Stem cell; Transit amplifying cell; p63