JOURNAL ARTICLE

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

Shenghong Yang, Matthew A Nugent, Mikhail P Panchenko
American Journal of Physiology. Lung Cellular and Molecular Physiology 2008, 295 (1): L143-51
18441095
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.

Full Text Links

Find Full Text Links for this Article

Discussion

You are not logged in. Sign Up or Log In to join the discussion.

Related Papers

Remove bar
Read by QxMD icon Read
18441095
×

Save your favorite articles in one place with a free QxMD account.

×

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"