Slug regulates integrin expression and cell proliferation in human epidermal keratinocytes.
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.
Turner
Frances E
FE
School of Biosciences, University of Birmingham, Edgbaston B15 2TT, United Kingdom.
Broad
Simon
S
Cancer Research UK, 44 Lincoln's Inn Fields, London WC2A 3PX, United Kingdom.
Khanim
Farhat L
FL
School of Biosciences, University of Birmingham, Edgbaston B15 2TT, United Kingdom.
Jeanes
Alexa
A
School of Biosciences, University of Birmingham, Edgbaston B15 2TT, United Kingdom.
Talma
Sonia
S
School of Biosciences, University of Birmingham, Edgbaston B15 2TT, United Kingdom.
Hughes
Sharon
S
School of Medicine, University of Birmingham, Edgbaston B15 2TT, United Kingdom.
Tselepis
Chris
C
School of Medicine, University of Birmingham, Edgbaston B15 2TT, United Kingdom.
Hotchin
Neil A
NA
School of Biosciences, University of Birmingham, Edgbaston B15 2TT, United Kingdom. Electronic address: n.a.hotchin@bham.ac.uk.
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
D015820:Cadherins; D015815:Cell Adhesion Molecules; D016023:Integrins; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D000097794:Kalinin; C000604407:SNAI1 protein, human