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Cell Growth & Differentiation Vol. 10, 255-262, April 1999
© 1999 American Association for Cancer Research

Cell Type and Gene-specific Activity of the Retinoid Inverse Agonist AGN 193109: Divergent Effects from Agonist at Retinoic Acid Receptor {gamma} in Human Keratinocytes

Scott M. Thacher1, Sunil Nagpal, Elliott S. Klein, Taghreed Arefieg, Glenn Krasinski, Dan DiSepio, Chapla Agarwal, Alan Johnson, Richard L. Eckert and Roshantha A. S. Chandraratna1

Departments of Biology [S. M. T., S. N., E. S. K., T. A., G. K., D. D., R. A. S. C.] and Chemistry [A. J., R. A. S. C.], Retinoid Research, Allergan, Irvine, California 92623, and Department of Physiology and Biophysics, Case Western Reserve, Cleveland, Ohio 44106 [C. A., R. L. E.]

Retinoids are important regulators of epithelial differentiation. AGN 193109 is a high-affinity antagonist and inverse agonist for the nuclear retinoic acid receptors (RARs). Paradoxically, both AGN 193109 and retinoid agonists inhibit the expression of the differentiation marker MRP-8 in normal human keratinocytes (NHKs). TTNPB, an RAR agonist, and AGN 193109 mutually antagonize MRP-8 inhibition at both mRNA and protein levels. We find that this antagonism, which is greatest at an AGN 193109:TTNPB ratio of about 10:1, is absent when either compound is in significant excess. The potent RAR{alpha}-specific agonist, AGN 193836, has no effect on MRP-8 regulation. These data indicate that inverse agonists and agonists suppress MRP-8 in NHKs through RAR{gamma} using distinct and mutually inhibitory mechanisms. The activity of AGN 193109 on MRP-8 is cell type specific. In differentiating ECE16-1 cervical cells, TTNPB inhibits while AGN 193109 induces MRP-8 mRNA levels. The effect of AGN 193109 on genes inhibited by retinoid agonists in NHKs is also selective; expression of the differentiation markers transglutaminase 1 and keratin 6 is not down-regulated by AGN 193109 whereas stromelysin-1 expression is suppressed. These results show a complex gene and cell context-specific interplay between agonist and inverse agonist for the regulation of gene expression.




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Molecular Cancer Research Cell Growth & Differentiation
Copyright © 1999 by the American Association of Cancer Research.