Catania, Annunziata (2006) Selective transcription and cellular proliferation induced by PDGF require histone deacetylase activity. [Tesi di dottorato] (Unpublished)
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|Item Type:||Tesi di dottorato|
|Uncontrolled Keywords:||Tyrosine kinase receptors; Phosphorylation; Histone deacetylases inhibitors; STAT activation; Oncogenes|
|Date Deposited:||30 Jul 2008|
|Last Modified:||30 Apr 2014 19:24|
Histone deacetylases (HDACs) are key regulatory enzymes involved in the control of gene expression in any cell type, and their inhibition by specific drugs has been widely correlated to cell cycle arrest, terminal differentiation and apoptosis. Although some of these compounds gave already very promising results in Phase I and II clinical trials for a large array of tumors, the molecular targets responsible for their anti-tumoral activity are still largely unknown. Here, we investigated whether HDAC activity was required for PDGF-dependent signal transduction and cellular proliferation. Exposure of PDGF-stimulated NIH3T3 fibroblasts to the HDAC inhibitor trichostatin A (TSA) potently repressed the expression of a group of genes strongly correlated to PDGF-dependent cellular growth and pro-survival activity, namely c-myc, VEGF and bcl-XL. Moreover, we show that TSA interfered with STAT3-dependent transcriptional activity induced by PDGF, suggesting STAT proteins as mediators of HDAC activity on PDGF transcriptional responses. Still, neither phosphorylation nor nuclear translocation and DNA-binding of STAT3 were affected by using TSA to interfere with PDGF stimulation. Finally, TSA treatment resulted in the suppression of PDGF-dependent cell proliferation as scored by a bromodeoxyuridine (BrdU) incorporation assay. Our data indicate that inhibition of HDAC activity by specific pharmacological inhibitors antagonizes the mitogenic effect of PDGF, suggesting that these drugs may specifically act on the expression of growth-related, STAT-dependent, PDGF early- and late-responsive genes.
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