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This Article Full Text Full Text (PDF) All Versions of this Article: 295/1/L143    most recent 00289.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Yang, S. Articles by Panchenko, M. P. Search for Related Content PubMed PubMed Citation Articles by Yang, S. Articles by Panchenko, M. P.

EGF antagonizes TGF-β-induced tropoelastin expression in lung fibroblasts via stabilization of Smad corepressor TGIF

Departments of ¹Biochemistry and ²Ophthalmology, Boston University School of Medicine, and ³Department of Biomedical Engineering, Boston University, Boston, Massachusetts

Submitted 25 July 2007 ; accepted in final form 22 April 2008

We previously reported that neutrophil elastase (NE) downregulates transforming growth factor-β (TGF-β)-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-β signaling. We show that EGF does not prevent the TGF-β-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-β-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-β in lung fibroblasts by stabilizing the Smad transcriptional corepressor TGIF.

elastin; neutrophil elastase