Transglutaminases are a group of enzymes that catalyze the post-translational modification of both intracellular proteins. The enzymes catalyze both the covalent cross-linking of proteins and the covalent conjugation of polyamines to protein-bound glutamine residues. We have been interested in the role of transglutaminases in the function of cultured cells and have studied the regulation and distribution of the most abundant intracellular transglutaminase, tissue transglutaminase, in a variety of normal and transformed cells. We have found that tissue transglutaminase is particularly abundant in macrophages and the enzyme accumulates to high levels in these cells following exposure to homologous serum. We have identified the active component in serum as trans-retionic acid and have shown that retinoic acid can induce a very rapid and dramatic increase in the synthesis of tissue transglutaminase in peritoneal macrophages. We are now proposing to investigate in detail the molecular mechanisms involved in retinoic acid control of transglutaminase gene expression in macrophages. We will investigate the mechanism of delivery of retinoic acid to the macrophage and the role of receptor mediated endocytosis in this process. We will investigate the delivery of retinoic acid to the macrophage nucleus and the contribution of the cytoplasmic retinoic acid binding protein (CRABP) to induction of tissue transglutaminase. In a third set of studies we will prepare a cloned cDNA probe to tissue transglutaminase and use it to characterize the mechanism by which retinoic acid activates gene expression. From these studies we hope to gain a detailed understanding of retinoic acid control of transglutaminase expression in the macrophage.
