BACKGROUND: Transforming growth factor-beta1 (TGF-beta1), a key biological mediator following ionizing radiation, plays a role in a complex tissue reaction involved in local radiation-induced pathological damage. Knocking out Smad3 (S3KO), a downstream signaling intermediate in the TGF-beta pathway, in mice protects their skin from radiation damage as demonstrated by decreased epithelial acanthosis and dermal fibrosis as compared to Smad3 wild-type (S3WT) mice. OBJECTIVE: The present study was designed to investigate the molecular mechanisms contributing to increased radioprotection in the absence of Smad3. METHODS: Primary dermal fibroblasts derived from S3WT and KO mice were exposed to 5Gy ionizing radiation in vitro. Western blot analyses, immunocytochemistry, and reporter transfections were used to dissect the radiation-induced events. RESULTS: There was increased phosphorylation of ERK-MAPK, p53 and H2A.X in S3KO compared to the S3WT fibroblasts, implicating them in a key signaling cascade in response of these cells to radiation. Pro-fibrotic gene expression was decreased in S3KO fibroblasts post-irradiation. CONCLUSION: The absence of Smad3 may decrease radio-responsiveness by increasing activation of DNA damage sensing mechanisms and decreasing induction of pro-fibrotic genes.
BACKGROUND:Transforming growth factor-beta1 (TGF-beta1), a key biological mediator following ionizing radiation, plays a role in a complex tissue reaction involved in local radiation-induced pathological damage. Knocking out Smad3 (S3KO), a downstream signaling intermediate in the TGF-beta pathway, in mice protects their skin from radiation damage as demonstrated by decreased epithelial acanthosis and dermal fibrosis as compared to Smad3 wild-type (S3WT) mice. OBJECTIVE: The present study was designed to investigate the molecular mechanisms contributing to increased radioprotection in the absence of Smad3. METHODS: Primary dermal fibroblasts derived from S3WT and KO mice were exposed to 5Gy ionizing radiation in vitro. Western blot analyses, immunocytochemistry, and reporter transfections were used to dissect the radiation-induced events. RESULTS: There was increased phosphorylation of ERK-MAPK, p53 and H2A.X in S3KO compared to the S3WT fibroblasts, implicating them in a key signaling cascade in response of these cells to radiation. Pro-fibrotic gene expression was decreased in S3KO fibroblasts post-irradiation. CONCLUSION: The absence of Smad3 may decrease radio-responsiveness by increasing activation of DNA damage sensing mechanisms and decreasing induction of pro-fibrotic genes.
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Authors: M S Anscher; T Murase; D M Prescott; L B Marks; H Reisenbichler; G C Bentel; D Spencer; G Sherouse; R L Jirtle Journal: Int J Radiat Oncol Biol Phys Date: 1994-10-15 Impact factor: 7.038
Authors: Tomer Avraham; Alan Yan; Jamie C Zampell; Sanjay V Daluvoy; Adriana Haimovitz-Friedman; Andrew P Cordeiro; Babak J Mehrara Journal: Am J Physiol Cell Physiol Date: 2010-06-02 Impact factor: 4.249
Authors: Kathleen C Flanders; Benjamin M Ho; Praveen R Arany; Christina Stuelten; Mizuko Mamura; Miya Okada Paterniti; Anastasia Sowers; James B Mitchell; Anita B Roberts Journal: Am J Pathol Date: 2008-05-23 Impact factor: 4.307