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J Cell Sci. 2014 Dec 15;127(Pt 24):5261-72. doi: 10.1242/jcs.156778. Epub 2014 Oct 24.

Epiprofin orchestrates epidermal keratinocyte proliferation and differentiation.

Author information

1
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.
2
Laboratory of Cell and Developmental Biology, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.
3
Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.
4
Division of Pediatric Dentistry, Department of Oral Health and Development Sciences, Tohoku University Graduate School of Dentistry, Sendai 980-8575, Japan.
5
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.

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.

KEYWORDS:

Differentiation; Keratinocyte; Notch; Proliferation; Skin development; Sp transcription factor; Stem cell; Transit amplifying cell; p63

PMID:
25344255
PMCID:
PMC4265740
DOI:
10.1242/jcs.156778
[Indexed for MEDLINE]
Free PMC Article

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