Retinoids are a class of lipid molecules that have dramatic effects on the growth and differentiation of both normal and neoplastic cells. These properties form the rationale for their potential use as chemopreventitive and chemotherapeutic agents. However, the moleculkar events by which retinoids, particularly retinoic-acid, alter cellular funcitons are poorly understood. We have recently demonstrated that retinoic acid acts as a direct and acute regulator of the expession of a specific enzyme, tissue transglutaminase, in mouse and human myeloid cells. Retinoic acid also induces the expression of a second, as yet unidentified, mouse mcarophage protein of 38,000 MW. We propose to take advantage of the effects of retinoic acid on these two specific murine genes in order to investigate the molecular mechanisms by which retinoids control gene expression. In order to accomplish this goal, we have prepared and cloned a partially purified mRNA from retinoic acid-induced mouse peritoneal macrophages. A tissue transglutaminase cDNA clone isolated from this library will be used to isolate and characterize the mouse tissue ITAse gene. In a similar manner, the gene coding for the 38 KD retinoid-induced protein (RIP) will be isolated and characterized. Then the 5- flanking regions of these two genes will be sequenced and compared, in order to identify the regulatory sequences that may be involved in controlling these retinoid-activated mammalian genes. Ultimately, we will link these flanking sequences to a reporter gene coding sequence, and use these chimeric genes in transcription studies to identify the critical control regions that mediate retinoid control of gene expression. THe accomplishment of these goals will form the basis for subsequent studies into retinoid acid activation of specific macrophage genes, and yield knowledge fundamental to our understanding of the molecular mechanisms by which retinoids control cellular growth and differentiation.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA041829-01
Application #
3182560
Study Section
Endocrinology Study Section (END)
Project Start
1986-05-01
Project End
1989-04-30
Budget Start
1986-05-01
Budget End
1987-04-30
Support Year
1
Fiscal Year
1986
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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Kent, T A; Messina, J L; Weinstock, R S et al. (1994) Synergistic induction of gene 33 expression by retinoic acid and insulin. Endocrinology 134:2237-44
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