title: AKT1 provides an essential survival signal required for differentiation and stratification of primary human keratinocytes.
abstract: Keratinocyte differentiation and stratification are complex processes involving multiple signaling pathways, which convert a basal proliferative cell into an inviable rigid squame. Loss of attachment to the basement membrane triggers keratinocyte differentiation, while in other epithelial cells, detachment from the extracellular matrix leads to rapid programmed cell death or anoikis. The potential role of AKT in providing a survival signal necessary for stratification and differentiation of primary human keratinocytes was investigated. AKT activity increased during keratinocyte differentiation and was attributed to the specific activation of AKT1 and AKT2. Targeted reduction of AKT1 expression, but not AKT2, by RNA interference resulted in an abnormal epidermis in organotypic skin cultures with a thin parabasal region and a pronounced but disorganized cornified layer. This abnormal stratification was due to significant cell death in the suprabasal layers and was alleviated by caspase inhibition. Normal expression patterns of both early and late markers of keratinocyte differentiation were also disrupted, producing a poorly developed stratum corneum.
authors.affiliation: Department of Biochemistry & Biophysics, Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, USA.
authors.forename: Barry R
authors.initials: BR
authors.lastname: Thrash
authors.forename: Craig W
authors.initials: CW
authors.lastname: Menges
authors.forename: Robert H
authors.initials: RH
authors.lastname: Pierce
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: McCance
mesh_terms: D017209:Apoptosis; D061945:Caspase Inhibitors; D002454:Cell Differentiation; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D020287:In Situ Nick-End Labeling; D007231:Infant, Newborn; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction; D012867:Skin / Q000166:cytology / Q000378:metabolism
chemical_list: D061945:Caspase Inhibitors; D034741:RNA, Small Interfering; C494918:AKT1 protein, human; C494921:AKT2 protein, human; C491754:AKT3 protein, human; D051057:Proto-Oncogene Proteins c-akt