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Signaling and Regulation

Identification and Characterization of Retinoic Acid Receptor ß₂ Target Genes in F9 Teratocarcinoma Cells¹

¹ Pharmacology Department, Weill Medical College of Cornell University, New York, NY, and
² Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, Collège de France, CU de Strasbourg, France

Requests for reprints: Lorraine J. Gudas, Room E409, Pharmacology Department, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10021. Phone: (212) 746-6250; Fax: (212) 746-8858. E-mail: ljgudas{at}med.cornell.edu

Retinoids, a group of natural and synthetic analogues of vitamin A (retinol), modulate the differentiation of many cell types. Retinoids are also used for the prevention and treatment of cancer. The actions of retinoids are generally mediated by the retinoic acid receptors (RARs , ß, and ) and the retinoid X receptors (RXRs , ß, and ). One of the RARs, RARß, is expressed at reduced levels in many human carcinomas, and F9 RARß₂^-/- cells do not growth arrest in response to RA. To determine if RARß₂ regulates the expression of a unique set of genes, through the use of subtractive hybridization and DNA array analysis, we have identified and characterized genes that are differentially expressed in F9 RARß₂^-/- teratocarcinoma cells. These genes, which encode transcription factors, cell surface signal transduction molecules, and metabolic enzymes, include c-myc, FOG1, GATA6, glutamate dehydrogenase, glutathione S-transferase homologue (p28), Foxq1, Hic5, Meis1a, Dab2, midkine, and the PDGF- receptor. These genes are regulated specifically by RARß₂ in F9 wild-type (Wt) cells as indicated by their expression profiles in F9 RARß₂^-/- cells as compared to F9 Wt, RAR^-/-, or RAR^-/- cells, and their responsiveness to specific retinoid receptor agonists. The basal expression levels of some of these genes, such as c-myc, are higher in the F9 RARß₂^-/- cells than in F9 Wt in the absence of exogenous retinoids, suggesting that RARß₂ can inhibit gene expression in the absence of a ligand. The RARß₂ target genes are transcriptionally activated by retinol, as well as RA, in F9 Wt cells. Because the lack of RARß₂ alters both the control of proliferation and differentiation in F9 cells, the genes that we have characterized may mediate key effects of RA, via RARß₂, on these processes.

Key Words: Retinoic acid • Retinoic acid receptor ß₂ • Subtractive hybridization • Microarray • Target genes

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