EGF SUPPRESSES TGF‐beta‐INDUCED ELASTOGENESIS IN LUNG FIBROBLASTS VIA STABILIZATION OF TGIF

Abstract

Elastin is a principal component of elastic fibers, which confer to the mature lung resilience and structural integrity. Once deposited, elastin displays a very slow turnover. Expression of tropoelastin, the precursor of elastin, is regulated by a variety of growth factors. TGF-β upregulates tropoelastin expression by increasing tropoelastin mRNA stability, whereas EGF downregulates tropoelastin expression by decreasing tropoelastin mRNA stability. Our previous studies demonstrated that EGF signals to destabilization of tropoelstin mRNA by activating EGFR/MEK/ERK pathway. The excessive degradation and inefficient repair of interstitial elastin are the hallmark of pulmonary emphysema. Biologically active EGF family growth factors and TGF-β are released by elastases in vivo and in vitro. In this report, we find that EGF suppresses tropoelastin expression through inhibition of TGF-β signaling. Interestingly, EGF does not prevent the TGF-β-induced nuclear accumulation of Smad2/3. However, EGF, by activating EGFR/MEK/ERK pathway, signals to stabilization of Smad corepressor TGIF. Increase in TGIF, either by overexpressing TGIF or by preventing its degradation with proteasome inhibitor, results in the inhibition of TGF-β-induced tropoelastin expression. We propose that EGF-dependent TGIF stabilization suppresses TGF-β-induced expression of an undefined factor, which affects tropoelastin mRNA stabiliy and elastogenesis in lung fibroblasts.