title: TGF-β1 accelerates the DNA damage response in epithelial cells via Smad signaling.
abstract: The evidence suggests that transforming growth factor-beta (TGF-β) regulates the DNA-damage response (DDR) upon irradiation, and we previously reported that TGF-β1 induced DNA ligase IV (Lig4) expression and enhanced the nonhomologous end-joining repair pathway in irradiated cells. In the present study, we investigated the effects of TGF-β1 on the irradiation-induced DDRs of A431 and HaCaT cells. Cells were pretreated with or without TGF-β1 and irradiated. At 30 min post-irradiation, DDRs were detected by immunoblotting of phospho-ATM, phospho-Chk2, and the presence of histone foci (γH2AX). The levels of all three factors were similar right after irradiation regardless of TGF-β1 pretreatment. However, they soon thereafter exhibited downregulation in TGF-β1-pretreated cells, indicating the acceleration of the DDR. Treatment with a TGF-β type I receptor inhibitor (SB431542) or transfections with siRNAs against Smad2/3 or DNA ligase IV (Lig4) reversed this acceleration of the DDR. Furthermore, the frequency of irradiation-induced apoptosis was decreased by TGF-β1 pretreatment in vivo, but this effect was abrogated by SB431542. These results collectively suggest that TGF-β1 could enhance cell survival by accelerating the DDR via Smad signaling and Lig4 expression.
authors.affiliation: Division of Basic Radiation Bioscience, Korea Institute of Radiation and Medical Sciences, Seoul, 01812, Republic of Korea.
authors.forename: Jeeyong
authors.initials: J
authors.lastname: Lee
authors.affiliation: Division of Basic Radiation Bioscience, Korea Institute of Radiation and Medical Sciences, Seoul, 01812, Republic of Korea.
authors.forename: Mi-Ra
authors.initials: MR
authors.lastname: Kim
authors.affiliation: Division of Basic Radiation Bioscience, Korea Institute of Radiation and Medical Sciences, Seoul, 01812, Republic of Korea.
authors.forename: Hyun-Ji
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Division of Basic Radiation Bioscience, Korea Institute of Radiation and Medical Sciences, Seoul, 01812, Republic of Korea.
authors.forename: You Sun
authors.initials: YS
authors.lastname: An
authors.affiliation: Division of Basic Radiation Bioscience, Korea Institute of Radiation and Medical Sciences, Seoul, 01812, Republic of Korea. Electronic address: yjy_71@kcch.re.kr.
authors.forename: Jae Youn
authors.initials: JY
authors.lastname: Yi
mesh_terms: D000818:Animals; D002460:Cell Line; D004249:DNA Damage / Q000187:drug effects / Q000528:radiation effects; D000072481:DNA Ligase ATP / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects*; D005260:Female; D005720:Gamma Rays; D006801:Humans; D008819:Mice, Nude; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects; D051785:Smad Proteins / Q000235:genetics / Q000378:metabolism*; D051899:Smad2 Protein / Q000235:genetics / Q000378:metabolism; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: C000607893:LIG4 protein, human; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; D051785:Smad Proteins; D051899:Smad2 Protein; D051900:Smad3 Protein; D053773:Transforming Growth Factor beta1; D000072481:DNA Ligase ATP
keywords: DNA damage response; Lig4; Radioprotection; Smads; TGF-β1