title: TIEG1 Represses Smad7-Mediated Activation of TGF-β1/Smad Signaling in Keloid Pathogenesis.
abstract: Transforming growth factor-β (TGF-β)/Smad signaling plays a key role in excessive fibrosis and keloid formations. Smad7 is a negative feedback regulator that prevents activation of TGF-β/Smad signaling. However, the regulatory mechanism for Smad7 in the keloid pathogenic process remains elusive. Here, we show that expression of TIEG1 is markedly higher in keloid fibroblasts, whereas protein, mRNA, and promoter activity levels of Smad7 are decreased. When TIEG1 was knocked down with small interfering RNA, both the promoter activity and protein expression of Smad7 were increased, whereas collagen production and the proliferation, migration, and invasion of keloid fibroblasts were decreased. In contrast, TIEG1 overexpression led to a decrease in Smad7 expression and Smad7 promoter activity. Upon TGF-β1 stimulation, TIEG1 promoted Smad2 phosphorylation by down-regulating Smad7. Luciferase reporter assays and chromatin immunoprecipitation assays further showed that TIEG1 can directly bind a GC-box/Sp1 site located between nucleotides -1392 and -1382 in the Smad7 promoter to repress Smad7 promoter activity. Taken together, these findings show that TIEG1 is highly expressed in human keloids and that it directly binds and represses Smad7 promoter-mediated activation of TGF-β/Smad2 signaling, thus providing clues for development of TIEG1 blocking strategies for therapy or prophylaxis of keloids.
authors.affiliation: Department of Burn and Plastic Surgery, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
authors.forename: Zhi-Cheng
authors.initials: ZC
authors.lastname: Hu
authors.affiliation: Department of Burn and Plastic Surgery, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
authors.forename: Fen
authors.initials: F
authors.lastname: Shi
authors.affiliation: Department of Burn and Plastic Surgery, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Liu
authors.affiliation: Department of Plastic Surgery, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Plastic Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
authors.forename: Dong
authors.initials: D
authors.lastname: Guo
authors.affiliation: Department of Burn and Plastic Surgery, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
authors.forename: Xiao-Ling
authors.initials: XL
authors.lastname: Cao
authors.affiliation: Department of Burn and Plastic Surgery, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
authors.forename: Chu-Fen
authors.initials: CF
authors.lastname: Chen
authors.affiliation: Department of Burn and Plastic Surgery, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
authors.forename: Shan-Qiang
authors.initials: SQ
authors.lastname: Qu
authors.affiliation: Department of Burn and Plastic Surgery, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
authors.forename: Jia-Yuan
authors.initials: JY
authors.lastname: Zhu
authors.affiliation: Department of Burn and Plastic Surgery, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China. Electronic address: tangbing@mail.sysu.edu.cn.
authors.forename: Bing
authors.initials: B
authors.lastname: Tang
mesh_terms: D000293:Adolescent; D000328:Adult; D016022:Case-Control Studies; D003094:Collagen / Q000378:metabolism; D015536:Down-Regulation; D051765:Early Growth Response Transcription Factors / Q000235:genetics*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006801:Humans; D007627:Keloid / Q000235:genetics / Q000473:pathology*; D051741:Kruppel-Like Transcription Factors / Q000235:genetics*; D008297:Male; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism*; D051906:Smad7 Protein / Q000235:genetics*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D055815:Young Adult
chemical_list: D051765:Early Growth Response Transcription Factors; C098111:KLF10 protein, human; D051741:Kruppel-Like Transcription Factors; D012333:RNA, Messenger; C497782:SMAD2 protein, human; C497806:SMAD7 protein, human; D051899:Smad2 Protein; D051906:Smad7 Protein; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D003094:Collagen