title: Transcriptional signature of epidermal keratinocytes subjected to in vitro scratch wounding reveals selective roles for ERK1/2, p38, and phosphatidylinositol 3-kinase signaling pathways.
abstract: Covering denuded dermal surfaces after injury requires migration, proliferation, and differentiation of skin keratinocytes. To clarify the major traits controlling these intermingled biological events, we surveyed the genomic modifications occurring during the course of a scratch wound closure of cultured human keratinocytes. Using a DNA microarray approach, we report the identification of 161 new markers of epidermal repair. Expression data, combined with functional analysis performed with specific inhibitors of ERK, p38(MAPK) and phosphatidylinositol 3-kinase (PI3K), demonstrate that kinase pathways exert very selective functions by precisely controlling the expression of specific genes. Inhibition of the ERK pathway totally blocks the wound closure and inactivates many early transcription factors and EGF-type growth factors. p38(MAPK) inhibition only delays "healing," probably in line with the control of genes involved in the propagation of injury-initiated signaling. In contrast, PI3K inhibition accelerates the scratch closure and potentiates the scratch-dependent stimulation of three genes related to epithelial cell transformation, namely HAS3, HBEGF, and ETS1. Our results define in vitro human keratinocyte wound closure as a repair process resulting from a fine balance between positive signals controlled by ERK and p38(MAPK) and negative ones triggered by PI3K. The perturbation of any of these pathways might lead to dysfunction in the healing process, similar to those observed in pathological wounding phenotypes, such as hypertrophic scars or keloids.
authors.affiliation: INSERM, U634, 28 Avenue de Valombrose, F-06107 Nice cedex 2, France.
authors.forename: Giorgos
authors.initials: G
authors.lastname: Fitsialos
authors.forename: Anne-Amandine
authors.initials: AA
authors.lastname: Chassot
authors.forename: Laurent
authors.initials: L
authors.lastname: Turchi
authors.forename: Manal A
authors.initials: MA
authors.lastname: Dayem
authors.forename: Kevin
authors.initials: K
authors.lastname: LeBrigand
authors.forename: Chimène
authors.initials: C
authors.lastname: Moreilhon
authors.forename: Guerrino
authors.initials: G
authors.lastname: Meneguzzi
authors.forename: Roser
authors.initials: R
authors.lastname: Buscà
authors.forename: Bernard
authors.initials: B
authors.lastname: Mari
authors.forename: Pascal
authors.initials: P
authors.lastname: Barbry
authors.forename: Gilles
authors.initials: G
authors.lastname: Ponzio
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D020405:Dermis / Q000201:enzymology* / Q000293:injuries* / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D015894:Genome, Human; D006801:Humans; D007627:Keloid / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D015603:Keratinocytes / Q000201:enzymology* / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000235:genetics; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D014945:Wound Healing / Q000187:drug effects / Q000235:genetics
chemical_list: D015415:Biomarkers; D004791:Enzyme Inhibitors; D019869:Phosphatidylinositol 3-Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3