EGF antagonizes TGF-beta-induced tropoelastin expression in lung fibroblasts via stabilization of Smad corepressor TGIF.
We previously reported that neutrophil elastase (NE) downregulates transforming growth factor-beta (TGF-beta)-maintained tropoelastin mRNA levels in lung fibroblasts through transactivation of the epidermal growth factor (EGF) receptor (EGFR)/Mek/Erk pathway, which is dependent on the NE-initiated release of soluble EGFR ligands. In the present study, we investigated the mechanism by which EGF downregulates tropoelastin expression. We found that EGF downregulates tropoelastin expression through inhibition of TGF-beta signaling. We show that EGF does not prevent the TGF-beta-induced nuclear accumulation of Smad2/3; rather, EGF stabilizes the short-lived Smad transcriptional corepressor TG-interacting factor (TGIF) via EGFR/Mek/Erk-mediated phosphorylation of TGIF. Elevation of TGIF levels, either by TGIF overexpression or prevention of TGIF degradation, is sufficient to inhibit TGF-beta-induced tropoelastin expression. Moreover, TGIF is essential for EGF-mediated downregulation of tropoelastin expression, inasmuch as small interfering RNA knockdown of TGIF blocked EGF-induced downregulation of tropoelastin. Finally, we demonstrated that NE treatment, which releases EGF-like growth factors, causes stabilization of TGIF through the EGFR/Mek/Erk pathway. These results suggest that EGFR/Mek/Erk signaling specifically antagonizes the proelastogenic action of TGF-beta in lung fibroblasts by stabilizing the Smad transcriptional corepressor TGIF.
Yang
Shenghong
S
Department of Biochemistry, Boston University School of Medicine, 715 Albany St, Boston, Massachusetts 02118, USA.
Nugent
Matthew A
MA
Panchenko
Mikhail P
MP
D000818:Animals; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004815:Epidermal Growth Factor / Q000378:metabolism* / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D019272:Leukocyte Elastase / Q000378:metabolism; D008168:Lung / Q000166:cytology / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012097:Repressor Proteins / Q000378:metabolism*; D051785:Smad Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014333:Tropoelastin / Q000096:biosynthesis*
D018398:Homeodomain Proteins; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D051785:Smad Proteins; C097504:TGIF1 protein, human; C490797:Tgif1 protein, mouse; D016212:Transforming Growth Factor beta; D014333:Tropoelastin; D004815:Epidermal Growth Factor; C512478:EGFR protein, human; C483803:Egfr protein, rat; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D020930:MAP Kinase Kinase Kinases; D019272:Leukocyte Elastase