A combined biological and bioinformatics approach for the analysis of transcription factors regulated by PDGF
(2010)
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- Authors
- Supervisors
- Demoulin, Jean-Baptiste
- Abstract
- (en) During this work, we developed TFactS (www.tfacts.org), a bioinformatics tool that predicts the activation (or inhibition) of transcription factors based on a list of regulated genes generated by expression microarrays. Using Fisher's statistics, TFactS compares a list of regulated genes with a database of transcription factors associated with well-established target genes. This approach is an alternative to the systematic analysis of gene promoters using consensus transcription factor binding sites. We showed that it can be used to analyze published cancer microarray data. TFactS was validated experimentally by analyzing gene regulation by platelet-derived growth factor (PDGF) receptors. PDGF stimulates cell migration and proliferation in wound healing, angiogenesis and embryogenesis, as well as in different types of cancers. We performed microarrays to identify genes regulated by PDGF receptors in fibroblasts and leukemic cells. TFactS suggested that PDGF activates transcription factors of the STAT and SREBP families, in line with our experimental data. TFactS has also predicted an inhibition of Forkhead box O (FOXO) transcription factors. It was already known that PDGF inhibits these factors by stimulating their phosphorylation by AKT. Our data demonstrate that PDGF also represses the expression of FOXO genes at the mRNA level. We showed that FOXO3 and FOXO1 can bind to FOXO1 gene promoter and stimulate FOXO1 mRNA transcription in a positive feed-back loop that is disrupted by growth factors. This process contributes to the growth promoting activity of PDGF. The data also suggest a mechanism by which growth factors may down-regulate FOXO genes in tumors. In conclusion, this work describes a new approach for transcription factor mining in microarray expression data. This allowed us to decipher the transcriptional regulations triggered by PDGF receptor signaling. This tool may contribute to the global analysis of transcriptional networks in cancer cells.
- Affiliations
Citations
Essaghir, A. (2010). A combined biological and bioinformatics approach for the analysis of transcription factors regulated by PDGF. https://hdl.handle.net/2078.5/130205