The regulation of cell differentiation by retinoic acid (Meeting abstract).

Important note: Information in this article was accurate in 1995. The state of the art may have changed since the publication date.

The regulation of cell differentiation by retinoic acid (Meeting abstract).

Proc Annu Meet Am Assoc Cancer Res; 35:668-9 1994. Unique Identifier : AIDSLINE ICDB/95606255
Gudas LJ; Langston A; Boylan J; Hosler B; Hu L; Dept. of Pharmacology, Cornell Univ. Medical Coll., New York, NY; 10021

Abstract: Retinoic acid (RA), a derivative of retinol (vitamin A), influences the proliferation and cellular differentiation of a wide variety of cell types; RA also exhibits striking effects on vertebrate development. When F9 cells differentiate, genes such as those encoding laminin B1 and collagen type IV(alpha 1) are transcriptionally activated between 24 and 48 hr after exposure to RA. In contrast, within 2 hr after RA addition the ERA-l/Hox 1.6 gene (now renamed Hox a1) is transcriptionally activated; the Hox a1 gene encodes a homeobox protein, a transcription factor involved in the control of gene expression. One of the retinoic acid receptor genes, RAR beta, is also rapidly transcriptionally activated in response to RA. Rapid decreases in the expression of genes encoding transcription factors such as REX-I also occur at the transcriptional level in response to retinoic acid. We have shown that the RA activation of the Hox a1 gene is controlled through the activity of an enhancer that contains an RARE to which RA receptors bind; however, other sequences also influence the activity of this enhancer, suggesting the presence of binding sites for novel proteins which regulate Hox a1 expression. Experiments in F9 cells with Hox a1 minigenes in which lacZ expression is controlled by the Hox a1 promoter and enhancer demonstrate that it is the 3' enhancer which confers RA responsiveness on the endogenous Hox a1 promoter, as constructs which lack the enhancer do not respond to RA. Recent analyses of two F9 cell lines, one RAR gamma-/- and one RAR (alpha-/- (lines in which both chromosomal copies of the genes have been disrupted by homologous recombination)), have shown that the RAR gamma gene is required for the activation of both the Hox a1 and laminin B1 genes, but not for activation of the Hox 2.9 (b1) gene. Our results strongly suggest that different clusters of homeobox genes on different chromosomes are regulated by specific and unique RARs. The expression of certain growth factor genes is also preferentially regulated by RAR gamma Preliminary analyses of the mechanism by which the expression of the REX-1 gene is regulated at the transcriptional level have also been carried out in F9 cells. The REX-1 gene encodes a transcription factor with four zinc fingers. We have isolated genomic DNA for the REX-1 gene, characterized the gene structure, and mapped it to mouse chromosome 8. Promoter elements contributing to the regulation of the REX-1 promoter in F9 cells have also been identified. A region required for REX-1 promoter activity in F9 stem cells contains an octamer motif (ATTTGCAT), a binding site for 'octamer' transcription factor members of the POU domain family of DNA-binding proteins. REX-1 promoter/CAT reporter plasmids including this octamer site exhibit reduced expression in F9 cells treated with RA. Thus, the octamer motif is a regulatory element required for the activity of the REX-1 promoter in F9 stem cells, and this motif contributes to the negative regulation by RA of the transcription of the REX-1 gene. Direct interaction of RA/receptor complexes with Hox a1 DNA is required for positive activation of the Hox a1 gene, whereas RA/receptor complexes presumably antagonize octamer transcription factors to inhibit the expression of the REX-1 gene. We have also analyzed the actions of retinoids in normal human epithelial cells and their neoplastically transformed derivatives, squamous cell carcinomas (SCCs). We have evidence that many SCC lines exhibit abnormally low expression of one of the retinoic acid receptor genes, RAR beta, and we are attempting to determine the reason for this low RAR expression. (7 Refs)

Keywords: Cell Differentiation/*DRUG EFFECTS Gene Expression Regulation, Neoplastic Gene Products, rex/GENETICS Genes, Homeobox/GENETICS Promoter Regions (Genetics) Receptors, Retinoic Acid/GENETICS Teratocarcinoma/*GENETICS/PATHOLOGY Transcription, Genetic Tretinoin/*PHARMACOLOGY ABSTRACT
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