J Biol Chem, Vol. 274, Issue 7, 4213-4219, February 12, 1999

TGF-3, but Not TGF-1, Protects Keratinocytes against 12-O-Tetradecanoylphorbol-13-acetate-induced Cell Death in Vitro and in Vivo

Jie Li, Kerstin Foitzik, Enzo Calautti, Howard Baden, Tom Doetschman^¶, and G. Paolo Dotto

From the  Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129 and^¶ Department of Molecular Genetics Biochemistry and Microbiology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267-0524

We have examined the role that individual TGF- isoforms, and in particular TGF-3, play in control of epidermal homeostasis. Mice with a knockout mutation of the TGF-3 gene die a few hours after birth. A full-thickness skin grafting approach was used to investigate the postnatal development and homeostatic control of the skin of these mice. Grafted skin of mice with a disruption of the TGF-3 gene developed similarly to grafts of wild type and TGF-1 knockout animals. However, a strikingly different response was observed after acute treatment with the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). When exposed to TPA, the grafted skin of wild type and TGF-1 knockout mice underwent a hyperplastic response similar to that of normal mouse skin. In marked contrast, TPA treatment of TGF-3 knockout grafts induced widespread areas of keratinocyte cell death. Analysis of cultured keratinocytes treated with purified TGF- isoforms revealed that TGF-3 plays a direct and specific function in protecting keratinocytes against TPA-induced cell death. The protective function of TGF-3 on TPA-induced cell death was not because of general suppression of the signaling pathways triggered by this agent, as ERK1/2 activation occurred to a similar if not greater extent in TGF-3-treated versus control keratinocytes. Instead, TGF-3 treatment led to a significant reduction in TPA-induced c-Jun N-terminal kinase activity, which was associated and possibly explained by specific counteracting effects of TGF-3 on TPA-induced disruption of keratinocyte focal adhesions.