RGD Reference Report - EGF antagonizes TGF-beta-induced tropoelastin expression in lung fibroblasts via stabilization of Smad corepressor TGIF. - Rat Genome Database

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

Authors: Yang, S  Nugent, MA  Panchenko, MP 
Citation: Yang S, etal., Am J Physiol Lung Cell Mol Physiol. 2008 Jul;295(1):L143-51. Epub 2008 Apr 25.
RGD ID: 2317192
Pubmed: PMID:18441095   (View Abstract at PubMed)
PMCID: PMC2494790   (View Article at PubMed Central)
DOI: DOI:10.1152/ajplung.00289.2007   (Journal Full-text)

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.



Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Tgif1Ratcellular response to growth factor stimulus  IEP EGFRGD 
Tgif1Ratnegative regulation of gene expression  IMP tropoelastinRGD 

Objects Annotated

Genes (Rattus norvegicus)
Tgif1  (TGFB-induced factor homeobox 1)


Additional Information