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 Citations (Scopus)

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

Fingerprint

Tetradecanoylphorbol Acetate
Cell death
Keratinocytes
Acetates
Cell Death
Skin
Grafts
Protein Isoforms
Genes
Transplants
Skin Transplantation
Focal Adhesions
JNK Mitogen-Activated Protein Kinases
In Vitro Techniques
Knockout Mice
Carcinogens
Animals
Homeostasis
Therapeutics
Adhesion

ASJC Scopus subject areas

  • Biochemistry

Cite this

TGF-β3, but not TGF-β1, protects keratinocytes against 12-O- tetradecanoylphorbol-13-acetate-induced cell death in vitro and in vivo. / Li, Jie; Foitzik, Kerstin; Calautti, Enzo; Baden, Howard; Doetschman, Tom; Dotto, G. Paolo.

In: Journal of Biological Chemistry, Vol. 274, No. 7, 12.02.1999, p. 4213-4219.

Research output: Contribution to journalArticle

Li, Jie ; Foitzik, Kerstin ; Calautti, Enzo ; Baden, Howard ; Doetschman, Tom ; Dotto, G. Paolo. / TGF-β3, but not TGF-β1, protects keratinocytes against 12-O- tetradecanoylphorbol-13-acetate-induced cell death in vitro and in vivo. In: Journal of Biological Chemistry. 1999 ; Vol. 274, No. 7. pp. 4213-4219.
@article{c04ef4a662d34cbc8698285a76de505f,
title = "TGF-β3, but not TGF-β1, protects keratinocytes against 12-O- tetradecanoylphorbol-13-acetate-induced cell death in vitro and in vivo",
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.",
author = "Jie Li and Kerstin Foitzik and Enzo Calautti and Howard Baden and Tom Doetschman and Dotto, {G. Paolo}",
year = "1999",
month = "2",
day = "12",
doi = "10.1074/jbc.274.7.4213",
language = "English",
volume = "274",
pages = "4213--4219",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "7",

}

TY - JOUR

T1 - TGF-β3, but not TGF-β1, protects keratinocytes against 12-O- tetradecanoylphorbol-13-acetate-induced cell death in vitro and in vivo

AU - Li, Jie

AU - Foitzik, Kerstin

AU - Calautti, Enzo

AU - Baden, Howard

AU - Doetschman, Tom

AU - Dotto, G. Paolo

PY - 1999/2/12

Y1 - 1999/2/12

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=0033547875&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0033547875&partnerID=8YFLogxK

U2 - 10.1074/jbc.274.7.4213

DO - 10.1074/jbc.274.7.4213

M3 - Article

VL - 274

SP - 4213

EP - 4219

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 7

ER -