1. TNFα Modulates Fibroblast Growth Factor Receptor 2 Gene Expression through the pRB/E2F1 Pathway: Identification of a Non-Canonical E2F Binding Motif
- Author
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Cinzia Marchese, Antonio Angeloni, Enrica Vescarelli, Simona Ceccarelli, Ferdinando Romano, Sirio D'Amici, and Luigi Frati
- Subjects
Anatomy and Physiology ,tnf alpha ,prb/e2f1 pathway ,fibroblast receptor 2 ,lcsh:Medicine ,Fibroblast growth factor ,Biochemistry ,chemistry.chemical_compound ,Molecular cell biology ,Immune Physiology ,Tyrosine Kinase Signaling Cascade ,E2F1 ,Membrane Receptor Signaling ,lcsh:Science ,Promoter Regions, Genetic ,Multidisciplinary ,integumentary system ,Protein Kinase Signaling Cascade ,Signaling Cascades ,Cell biology ,Cytokines ,Keratinocyte growth factor ,Signal transduction ,Research Article ,Signal Transduction ,Protein Binding ,musculoskeletal diseases ,DNA transcription ,Blotting, Western ,Biology ,Real-Time Polymerase Chain Reaction ,Cell Growth ,Proinflammatory cytokine ,Cell Line ,Molecular Genetics ,Downregulation and upregulation ,Growth Factors ,Cell Line, Tumor ,Genetics ,Humans ,Immunoprecipitation ,Gene Regulation ,Receptor, Fibroblast Growth Factor, Type 2 ,E2F ,Fibroblast growth factor receptor 2 ,Tumor Necrosis Factor-alpha ,lcsh:R ,Proteins ,Molecular biology ,stomatognathic diseases ,chemistry ,Microscopy, Fluorescence ,lcsh:Q ,Gene expression ,E2F1 Transcription Factor - Abstract
Interactions between epithelium and mesenchyme during wound healing are not fully understood, but Fibroblast Growth Factors (FGFs) and their receptors FGFRs are recognized as key elements. FGFR2 gene encodes for two splicing transcript variants, FGFR2-IIIb or Keratinocyte Growth Factor Receptor (KGFR) and FGFR2-IIIc, which differ for tissue localization and ligand specificity. Proinflammatory cytokines play an essential role in the regulation of epithelial-mesenchymal interactions, and have been indicated to stimulate FGFs production. Here we demonstrated that upregulation of FGFR2 mRNA and protein expression is induced by the proinflammatory cytokines Tumor Necrosis Factor-α, Interleukin-1β and Interleukin 2. Furthermore, we found that TNFα determines FGFR2 transcriptional induction through activation of pRb, mediated by Raf and/or p38 pathways, and subsequent release of the transcription factor E2F1. Experiments based on FGFR2 promoter serial deletions and site-directed mutagenesis allowed us to identify a minimal responsive element that retains the capacity to be activated by E2F1. Computational analysis indicated that this element is a non-canonical E2F responsive motif. Thus far, the molecular mechanisms of FGFR2 upregulation during wound healing or in pathological events are not known. Our data suggest that FGFR2 expression can be modulated by local recruitment of inflammatory cytokines. Furthermore, since alterations in FGFR2 expression have been linked to the pathogenesis of certain human cancers, these findings could also provide elements for diagnosis and potential targets for novel therapeutic approaches. more...
- Published
- 2013