Nrf transcription factors in keratinocytes are essential for skin tumor prevention but not for wound healing.

The Nrf2 transcription factor is a key player in the cellular stress response through its regulation of cytoprotective genes. In this study we determined the role of Nrf2-mediated gene expression in keratinocytes for skin development, wound repair, and skin carcinogenesis. To overcome compensation by the related Nrf1 and Nrf3 proteins, we expressed a dominant-negative Nrf2 mutant (dnNrf2) in the epidermis of transgenic mice.

Keratinocytes from APP/APLP2-deficient mice are impaired in proliferation, adhesion and migration in vitro.

Growing evidence shows that the soluble N-terminal form (sAPPalpha) of the amyloid precursor protein (APP) represents an epidermal growth factor fostering keratinocyte proliferation, migration and adhesion. APP is a member of a protein family including the two mammalian amyloid precursor-like proteins APLP1 and APLP2. In the mammalian epidermis, only APP and APLP2 are expressed.

Cytoprotective function of sAppalpha in human keratinocytes.

sAPPalpha, the soluble form of the beta-amyloid precursor protein, has been shown to act as a potent epidermal growth factor by stimulating keratinocyte proliferation and migration. In this report we provide evidence for a cytoprotective role of sAPPalpha. As a model we used HaCaT cells and normal human keratinocytes (NHK) cultured in the absence of fetal calf serum and bovine pituitary extract.

Biological roles of APP in the epidermis.

The amyloid precursor protein (APP) was initially detected in cells of the central nervous system where it is considered to be involved in the pathogenesis of Alzheimer's disease. However, APP is also found in peripheral organs with exceptionally strong expression in the mammalian epidermis where it fulfils a variety of distinct biological roles. Full length APP appears to facilitate keratinocyte adhesion due to its ability to interact with the extracellular matrix.

Normalized proliferation of normal and psoriatic keratinocytes by suppression of sAPPalpha-release.

The soluble form of the beta-amyloid precursor protein (sAPPalpha) is known to function in the autocrine regulation of epidermal growth and repair. Here we show that its proteolytic release by alpha-secretase in normal human keratinocytes is susceptible to hydroxamic-acid-based zinc metalloproteinase inhibitors and suppressed by these inhibitors by 80%-90%. As various other growth factors participate in regulating epidermal growth we investigated whether the inhibitor-induced sAPPalpha-deficiency would affect keratinocyte proliferation.

The influence of L-arginine on the regulation of epidermal arginase.

Topical preparations containing urea are firmly established in dermatological therapy and nursing care therapy. In addition, urea is frequently used as an inactive ingredient with disinfecting, keratoplastic and penetration-promoting action in topical preparations. Despite good tolerance and ensured action, particularly the irritating effect on erosive, exudative or strongly inflammatory skin restricts its application.