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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK027078-10
Application #
3228176
Study Section
Physiological Chemistry Study Section (PC)
Project Start
1980-04-01
Project End
1992-06-30
Budget Start
1990-07-01
Budget End
1991-06-30
Support Year
10
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of Texas Health Science Center Houston
Department
Type
Schools of Medicine
DUNS #
City
Houston
State
TX
Country
United States
Zip Code
77225
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Nagy, L; Saydak, M; Shipley, N et al. (1996) Identification and characterization of a versatile retinoid response element (retinoic acid receptor response element-retinoid X receptor response element) in the mouse tissue transglutaminase gene promoter. J Biol Chem 271:4355-65
Lu, S; Saydak, M; Gentile, V et al. (1995) Isolation and characterization of the human tissue transglutaminase gene promoter. J Biol Chem 270:9748-56
Fesus, L; Nagy, L; Basilion, J P et al. (1991) Retinoic acid receptor transcripts in human umbilical vein endothelial cells. Biochem Biophys Res Commun 179:32-8
Fesus, L; Davies, P J; Piacentini, M (1991) Apoptosis: molecular mechanisms in programmed cell death. Eur J Cell Biol 56:170-7
Gentile, V; Saydak, M; Chiocca, E A et al. (1991) Isolation and characterization of cDNA clones to mouse macrophage and human endothelial cell tissue transglutaminases. J Biol Chem 266:478-83
Chiocca, E A; Davies, P J; Stein, J P (1989) Regulation of tissue transglutaminase gene expression as a molecular model for retinoid effects on proliferation and differentiation. J Cell Biochem 39:293-304
Chiocca, E A; Davies, P J; Stein, J P (1988) The molecular basis of retinoic acid action. Transcriptional regulation of tissue transglutaminase gene expression in macrophages. J Biol Chem 263:11584-9
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Davies, P J; Basilion, J P; Chiocca, E A et al. (1988) Retinoids as generalized regulators of cellular growth and differentiation. Am J Med Sci 296:164-70