CHROMATIN ACTIVATION IN RETINOID-INDUCED APOPTOSIS

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Retinoids are metabolites of vitamin A that have profound effects on the growth, differentiation and death (apoptosis) of normal and neoplastic cells. While a lot has been learned of the mechanisms by which retinoids regulate cellular proliferation and differentiation remarkably little is known about the molecular mechanisms involved in retinoid - induced apoptosis. To address this problem, we were recently awarded an RO1 grant (CA76088) to investigate the signaling pathways involved in retinoid-induced apoptosis. These studies were designed to identify the retinoid receptors and signaling pathways (direct versus indirect effects) involved in the induction of the enzyme tissue transglutaminase in cells undergoing apoptosis in vivo. At the time this application was submitted it was not possible to investigate the molecular mechanism of these effects because little was known of the post-receptor mechanisms that linked ligand binding to transcriptional activation. In the interim however important progress has been made in this field with the discovery (based in part on the collaborating investigators findings) that ligand activation of retinoid receptors recruits proteins with histone acetyl transferase activity to the promoter of target genes. It has been hypothesized that alterations in chromatin structure secondary to histone acetylation may be an important contributor to the ligand - dependent activation of transcription. The experimental evidence in support of this hypothesis have been largely gathered in model systems. The goal of the studies included in this proposal will be to determine whether retinoid - dependent acetylation of chromatin contributes to the activation of gene expression in cells undergoing retinoid-induced apoptosis. The proposed studies will address two specific aims. The first will be to characterize retinoid -induced changes in chromatin structure in myeloid leukemia cells undergoing retinoid-induced apoptosis in vitro. The second aim will be to examine the effects of retinoids on chromatin structure in cells undergoing apoptosis during regression of the interdigital webs in vivo. The results of both of these studies should provide novel information on the role of historic acetylation and de-acetylation in cells undergoing apoptosis in vitro and in vivo.