CONCERTED ACTION OF TGF-BETA-1 AND ITS TYPE-II RECEPTOR IN CONTROL OFEPIDERMAL HOMEOSTASIS IN TRANSGENIC MICE

Transforming growth factor-beta 1 (TGF-beta 1) is a modulator of cellu lar proliferation, differentiation, and extracellular matrix depositio n. It is a potent epithelial growth inhibitor and can alter the differ entiative properties of keratinocytes, in vitro, but little is known a bout its normal physiological function in the epidermis in vivo. Trans genic mice were generated using a keratin 10 (K10) gene promoter to dr ive constitutive expression of TGF-beta 1 in the suprabasal keratinocy te compartment. Surprisingly, these mice showed a two- to threefold in crease in epidermal DNA labeling index over control mice, in the absen ce of hyperplasia. The transgene, however, acted in the expected fashi on, as a negative regulator of cell growth, when hyperplasia was induc ed by treatment by 12-tetradecanoyl-phorbol-13-acetate (TPA). Epiderma l TGF-beta type I and II receptor (T beta RI and T beta RII) levels we re examined in control and transgenic mice during induction of hyperpl asia by TPA. Whereas T beta RI levels remained relatively constant, T beta RII expression was strongly induced in TPA-treated skins, prior t o the induction of the growth inhibitory response to TGF-beta 1, and i ts level of expression correlated with growth sensitivity to TGF-beta 1 in vivo and in vitro. These results suggest that TGF-beta 1 and its type II receptor are part of the endogenous homeostatic regulatory mac hinery of the epidermis.