Selective transcription and cellular proliferation induced by PDGF require histone deacetylase activity

Catania, Annunziata (2006) Selective transcription and cellular proliferation induced by PDGF require histone deacetylase activity. [Tesi di dottorato] (Inedito)

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Abstract

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.

Tipologia di documento:Tesi di dottorato
Parole chiave:Tyrosine kinase receptors; Phosphorylation; Histone deacetylases inhibitors; STAT activation; Oncogenes
Settori scientifico-disciplinari MIUR:Area 06 Scienze mediche > MED/04 PATOLOGIA GENERALE
Coordinatori della Scuola di dottorato:
Coordinatore del Corso di dottoratoe-mail (se nota)
Avvedimento, Enrico Vittorio
Tutor della Scuola di dottorato:
Tutor del Corso di dottoratoe-mail (se nota)
Carlomagno, Maria Stella
Stato del full text:Accessibile
Data:2006
Numero di pagine:38
Istituzione:Università degli Studi di Napoli Federico II
Dipartimento o Struttura:Biologia e Patologia Cellulare e Molecolare “L. Califano”
Tipo di tesi:Dottorato
Stato dell'Eprint:Inedito
Denominazione del dottorato:Patologia e Fisiopatologia Molecolare
Ciclo di dottorato:XVII
Numero di sistema:779
Depositato il:30 Luglio 2008
Ultima modifica:04 Febbraio 2009 09:40

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