Overexpression of bone morphogenetic protein-6 (BMP-6) in murine epidermis suppresses skin tumor formation by induction of apoptosis and downregulation of fos/jun family members

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Abstract
Bone morphogenetic protein-6 (BMP-6) is a member of the transforming growth factor-ß superfamily. In murine skin, BMP-6 is highly expressed in postmitotic keratinocytes from day 15.5 p.c. till day 6 p.p. Expression in adult skin remains at very low levels, but pathological conditions such as wounding induce the expression of BMP-6. We demonstrate that tumor promotion by TPA (12-O-tetradecanoylphorbol-13-acetate) also induces expression of BMP-6 in suprabasal keratinocytes. This induction is due to post-transcriptional regulation since the level of BMP-6 mRNA remained unchanged. We performed two-stage skin carcinogenesis experiments with transgenic mice epidermally overexpressing BMP-6. These mice display augmented mitotic indices in normal and TPA-treated epidermis when compared to controls. Despite this hyperproliferation, BMP-6 transgenics showed a delayed development and strong suppression of benign and malignant skin tumor formation. In order to resolve this paradox we determined apoptotic frequencies as well as the expression of constituents of AP-1 (activator protein-1) which is essential for tumor promotion. A higher rate of apoptotic keratinocytes was detectable in transgenic mice versus controls and a downregulation of mRNA for jun/fos family members in transgenic skin after TPA-treatment. Thus expression of BMP-6 augments apoptosis and downregulates the transcription of AP-1 family members thereby establishing tumor resistance.