title: Slug regulates integrin expression and cell proliferation in human epidermal keratinocytes.
abstract: The human epidermis is a self-renewing epithelial tissue composed of several layers of keratinocytes. Within the epidermis there exists a complex array of cell adhesion structures, and many of the cellular events within the epidermis (differentiation, proliferation, and migration) require that these adhesion structures be remodeled. The link between cell adhesion, proliferation, and differentiation within the epidermis is well established, and in particular, there is strong evidence to link the process of terminal differentiation to integrin adhesion molecule expression and function. In this paper, we have analyzed the role of a transcriptional repressor called Slug in the regulation of adhesion molecule expression and function in epidermal keratinocytes. We report that activation of Slug, which is expressed predominantly in the basal layer of the epidermis, results in down-regulation of a number of cell adhesion molecules, including E-cadherin, and several integrins, including alpha3, beta1, and beta4. We demonstrate that Slug binds to the alpha3 promoter and that repression of alpha3 transcription by Slug is dependent on an E-box sequence within the promoter. This reduction in integrin expression is reflected in decreased cell adhesion to fibronectin and laminin-5. Despite the reduction in integrin expression and function, we do not observe any increase in differentiation. We do, however, find that activation of Slug results in a significant reduction in keratinocyte proliferation.
authors.affiliation: School of Biosciences, University of Birmingham, Edgbaston B15 2TT, United Kingdom.
authors.forename: Frances E
authors.initials: FE
authors.lastname: Turner
authors.affiliation: Cancer Research UK, 44 Lincoln's Inn Fields, London WC2A 3PX, United Kingdom.
authors.forename: Simon
authors.initials: S
authors.lastname: Broad
authors.affiliation: School of Biosciences, University of Birmingham, Edgbaston B15 2TT, United Kingdom.
authors.forename: Farhat L
authors.initials: FL
authors.lastname: Khanim
authors.affiliation: School of Biosciences, University of Birmingham, Edgbaston B15 2TT, United Kingdom.
authors.forename: Alexa
authors.initials: A
authors.lastname: Jeanes
authors.affiliation: School of Biosciences, University of Birmingham, Edgbaston B15 2TT, United Kingdom.
authors.forename: Sonia
authors.initials: S
authors.lastname: Talma
authors.affiliation: School of Medicine, University of Birmingham, Edgbaston B15 2TT, United Kingdom.
authors.forename: Sharon
authors.initials: S
authors.lastname: Hughes
authors.affiliation: School of Medicine, University of Birmingham, Edgbaston B15 2TT, United Kingdom.
authors.forename: Chris
authors.initials: C
authors.lastname: Tselepis
authors.affiliation: School of Biosciences, University of Birmingham, Edgbaston B15 2TT, United Kingdom. Electronic address: n.a.hotchin@bham.ac.uk.
authors.forename: Neil A
authors.initials: NA
authors.lastname: Hotchin
mesh_terms: D001483:Base Sequence; D015820:Cadherins / Q000096:biosynthesis; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000096:biosynthesis; D002454:Cell Differentiation; D049109:Cell Proliferation; D004789:Enzyme Activation; D000078404:Epidermal Cells; D006801:Humans; D016023:Integrins / Q000096:biosynthesis*; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism*; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000096:biosynthesis* / Q000737:chemistry; D000097794:Kalinin
chemical_list: D015820:Cadherins; D015815:Cell Adhesion Molecules; D016023:Integrins; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D000097794:Kalinin; C000604407:SNAI1 protein, human