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First published online 12 September 2006
doi: 10.1242/jcs.03175

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Regulation of epidermal homeostasis and repair by phosphoinositide 3-kinase

¹ Institute of Cell Biology, Department of Biology, ETH Zurich, CH-8093 Zurich, Switzerland
² Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
³ Molecular Oncology, Merck Research Laboratories, Boston, MA 02115, USA

^* Author for correspondence (e-mail: sabine.werner{at}cell.biol.ethz.ch)

Accepted 11 July 2006

The epidermis undergoes continuous self-renewal to maintain its protective function. Whereas growth factors are known to modulate overall skin homeostasis, the intracellular signaling pathways, which control the delicate balance between proliferation and differentiation in keratinocytes, are largely unknown. Here we show transient upregulation of the phosphoinositide 3-kinase (PI3K) catalytic subunits p110 and p110ß in differentiating keratinocytes in vitro, expression of these subunits in the epidermis of normal and wounded skin, and enhanced Akt phosphorylation in the hyperproliferative wound epidermis. Stimulation of PI3K activity in cultured keratinocytes by stable expression of an inducible, constitutively active PI3K mutant promoted cell proliferation and inhibited terminal differentiation in keratinocyte monocultures and induced the formation of a hyperplastic, disorganized and poorly differentiated epithelium in organotypic skin cultures. Activation of PI3K signaling also caused reorganization of the actin cytoskeleton and induced keratinocyte migration in vitro and in skin organ cultures. The identification of 122 genes, which are differentially expressed after induction of PI3K signaling provides insight into the molecular mechanisms underlying the observed effects of active PI3K on keratinocytes and indicates that hyperproliferation may be achieved at the expense of genome integrity. These results identify PI3K as an important intracellular regulator of epidermal homeostasis and repair.

Key words: Keratinocyte, Organotypic culture, Skin, Wound healing

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