RETINOID REGULATION OF TRANSGLUTAMINASE GENE EXPRESSION

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Retinoids are vitamin A metabolites that have profound effects on the growth, differentiation and death of both normal and neoplastic cells. The efficacy of retinoids as both chemopreventative and chemotherapeutic agents useful in the treatment of human cancers has lead to interest in the molecular mechanisms that underlie retinoid action. We have been interest in the ability of retinoids to induce apoptosis in neoplastic cells and have used the induction of the enzyme tissue transglutaminase as a molecular probe to investigate the mechanisms by which retinoids regulate gene expression. Tissue transglutaminase is a protein cross- linking enzyme that accumulates to high levels in apoptotic cells. The induction of transglutaminase in dying cells provides a unique opportunity to investigate the molecular mechanisms that control gene expression during apoptosis. We have isolated 4.0 kB of 5'-flanking DNA from the transglutaminase gene promoter and have shown in transgenic mice that this segment of the promoter includes all of the information necessary to direct the activation of the transglutaminase promoter in the apoptotic cells formed during normal limb development. We have demonstrated that retinoids are critical regulators of the transcriptional activity of this promoter and have identified two cis- regulatory elements, a tripartite retinoid response element (RRE1) and a conserved element (HR-1) that co-operate in regulating the transcriptional activity of this promoter. We have also demonstrated that both hetrodimeric RXR/RAR and homodimeric RXR/RXR complexes can bind to and activate transcription of the transglutaminase gene. The next step in our studies will be to evaluate the factors that control the expression of the transglutaminase gene in vivo, in cells undergoing apoptotic cell death during normal limb development. We will evaluate the retinoid receptor signaling pathways that control expression of this gene is apoptotic cells. We will also investigate the role of direct and indirect effects on the activation of transglutaminase expression. These studies should provide new insights into the molecular mechanisms involved in retinoid - induced apoptosis in vivo.