Retinoic acid receptor alpha suppresses polyomavirus transformation and c-fos expression in rat fibroblasts.
To explore the molecular mechanisms by which retinoic acid inhibits oncogenic transformation, we have examined the effects of retinoic acid on the polyomavirus-induced transformation of rat fibroblasts. Treatment of rat F111 fibroblasts with high concentrations of retinoic acid (10(-6) M) partially inhibited the ability of polyomavirus to induce dense focus formation (50-70%). This effect was not secondary to a retinoic acid-dependent block of cellular proliferation. To address the role of the retinoic acid receptor (RAR-alpha) in mediating the transformation-inhibitory effect of retinoic acid, we have overexpressed either RAR-alpha or cellular retinoic acid-binding protein I (CRABP) cDNAs in F111 cells. Introduction of a CRABP I expression vector did not alter the responsiveness of F111 cells to retinoic acid in any detectable fashion. In contrast, overexpression of RAR-alpha increased the sensitivity of F111 cells to the transformation-inhibitory action of retinoic acid by 10- to 100-fold. At high concentrations, retinoic acid inhibited transformation of F111-RAR cells by polyomavirus by about 90%. At near physiological concentrations, retinoic acid inhibited transformation by 25-50% in F111-RAR cells but not in control cells. Retinoic acid did not inhibit either the synthesis of polyoma middle T (mT) or pp60c-src, the cellular target for mT action, or the formation of mT:pp60c-src:PI-3 kinase (phosphatidylinositol-3 kinase) complexes. Therefore, RAR-alpha was not acting as a negative regulator of expression of either the polyomavirus middle T oncogene or the cellular proto-oncogene, c-src. It seems likely that RAR-alpha regulates the expression of cellular genes whose products interact in some way with mT-regulated signaling pathways, leading to a ligand-dependent suppression of polyoma transformation. In addition, RAR-alpha overexpression selectively inhibits the serum-stimulated expression of the c-fos gene, but does not affect the expression of a number of other serum- and polyomavirus-inducible genes including c-jun, junB, c-myc and actin.
Talmage
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Institute of Human Nutrition, Columbia University, New York, New York 10032.
Lackey
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D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000032:analysis; D001790:Blood Physiological Phenomena; D002352:Carrier Proteins / Q000502:physiology*; D002453:Cell Cycle; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D005347:Fibroblasts; D015870:Gene Expression; D016762:Genes, fos; D011120:Polyomavirus / Q000472:pathogenicity / Q000502:physiology*; D000090063:Proto-Oncogene Mas; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000032:analysis; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D018168:Receptors, Retinoic Acid; D014212:Tretinoin / Q000494:pharmacology
D000952:Antigens, Polyomavirus Transforming; D002352:Carrier Proteins; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; D014212:Tretinoin; D016392:Proto-Oncogene Proteins pp60(c-src)