ALTERED EPIDERMAL-CELL GROWTH-CONTROL IN-VIVO BY INDUCIBLE EXPRESSIONOF TRANSFORMING GROWTH-FACTOR-BETA-1 IN THE SKIN OF TRANSGENIC MICE

An inducible bovine KIV keratin gene promoter was used to target expr ession of latent or activated transforming growth factor beta 1 (TGF b eta 1) to keratinocytes in transgenic mice. This short (2.2-kb) kerati n 6 (K6) promoter element was generally silent in untreated animals bu t was induced in keratinocytes when placed in culture or, in vivo, in response to hyperplasia that follows topical application of the tumor promoter, 12-O-tetradecanoylphorbol-13-acetate. All of the K6-TGF beta 1 transgenic lines studied showed attenuation of the basal keratinocy te proliferative response to 12-O-tetradecanoylphorbol-13-acetate as a consequence of inducible TGF beta 1 gene expression. One of the six l ines studied showed constitutive transgene expression at low levels in the skin, and this line had a 2- to 3-fold increase in epidermal DNA labeling index over control mice. Although in vitro TGF beta 1 is know n to be a potent negative regulator of epithelial cell proliferation, in vivo TGF beta 1 has complex biological activities and can act as ei ther a positive or negative regulator of keratinocyte proliferation.