Transglutaminases are a group of enzymes that catalyze the covalent cross-linking of cellular proteins. We have been interested in the factors that regulate the expression of these enzymes in normal and leukemic myeloid cells. Previous studies from our laboratory have shown that physiological concentrations of retinoids can induce dramatic increases in the levels of a specific transglutaminase, tissue transglutaminase, in mouse peritoneal macrophages, human peripheral blood monocytes and human promyelocytic leukemia (HL-60) cells. In mouse macrophages retinoic acid can increase tissue transglutaminase mRNAS levels in minutes and can produce 50 to 100 - fold increases in the levels of the mRNA in 3 - 6 h. We propose to investigate the molecular mechanisms involved in the induction of transglutaminase in macrophages. We will study the role of transcriptional and post-transcriptional control in inducing transglutaminase mRNA. We will isolate the tissue transglutaminase gene, characterize it and identify the regions that control its basal and retinoid-stimulated expression in myeloid cells. We will also identify the macrophage proteins that bind retinoic acid and reconstruct the pathway involved in the induction of the enzyme. It is the goal of these studies to provide a detailed model of the molecular mechanisms involved in the induction of tissue transglutaminase in myeloid cells.
