TGF-β3, but not TGF-β1, 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, G. Paolo Dotto

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

We have examined the role that individual TGF-β isoforms, and in particular TGF-β3, play in control of epidermal homeostasis. Mice with a knockout mutation of the TGF-β3 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-β3 gene developed similarly to grafts of wild type and TGF-β1 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-β1 knockout mice underwent a hyperplastic response similar to that of normal mouse skin. In marked contrast, TPA treatment of TGF-β3 knockout grafts induced widespread areas of keratinocyte cell death. Analysis of cultured keratinocytes treated with purified TGF-β isoforms revealed that TGF-β3 plays a direct and specific function in protecting keratinocytes against TPA-induced cell death. The protective function of TGF- β3 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-β3-treated versus control keratinocytes. Instead, TGF-β3 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-β3 on TPA- induced disruption of keratinocyte focal adhesions.

Original languageEnglish (US)
Pages (from-to)4213-4219
Number of pages7
JournalJournal of Biological Chemistry
Volume274
Issue number7
DOIs
StatePublished - Feb 12 1999
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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