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.
Highlights
Despite detachment from the basement membrane and loss of integrin contacts, which is a potent apoptotic stimulus in most epithelial cells [4], the keratinocyte remains viable and metabolically active until reaching the interface of the granular and cornified layers, a region called the transition zone
AKT Activity Increases during Keratinocyte Differentiation—Differentiation-specific activation of AKT has been detected in various cell types including myocytes and adipocytes [13, 17]
Further examination of AKT activity during calcium-stimulated keratinocyte differentiation was accessed by Immunoprecipitation Kinase (IPK) assay using purified GSK3 fusion protein as a substrate
Summary
Despite detachment from the basement membrane and loss of integrin contacts, which is a potent apoptotic stimulus in most epithelial cells [4], the keratinocyte remains viable and metabolically active until reaching the interface of the granular and cornified layers, a region called the transition zone. Using RNA interference in combination with organotypic culture, the importance of AKT activity in human keratinocyte differentiation and skin formation was assessed in the work presented here.
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