Journal
JOURNAL OF CELL SCIENCE
Volume 119, Issue 19, Pages 4033-4046Publisher
COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.03175
Keywords
keratinocyte; organotypic culture; skin; wound healing
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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 alpha and p110 beta 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.
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