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J. Biol. Chem., Vol. 281, Issue 17, 12155-12162, April 28, 2006

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AKT1 Provides an Essential Survival Signal Required for Differentiation and Stratification of Primary Human Keratinocytes^*

Barry R. Thrash, Craig W. Menges, Robert H. Pierce^¶, and Dennis J. McCance^||¶1

From the Department of Biochemistry & Biophysics, Department of Pathology and Laboratory Medicine, ^||Department of Microbiology and Immunology, and ^¶The James P. Wilmot Cancer Center, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642

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.

Received for publication, November 10, 2005 , and in revised form, February 6, 2006.

^* This work was supported by National Institutes of Health Grant RO1 AI 30798 (to D. J. M.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: University of Rochester School of Medicine and Dentistry, 601 Elmwood Ave., Box 672, Rochester, NY 14642. Tel.: 585-275-0101; Fax: 585-473-9573; E-mail: dennis_mccance{at}urmc.rochester.edu.

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