The objective of this study was to determine whether the expression of specific oncogenes can influence the response of cells to retinoids. To test this idea we examined the effect of retinoic acid on several neoplastic cell lines that were clonally derived from immortal, non-tumorigenic Syrian hamster embryo DES-4 cells after transfection with v-src or v-Ha-ras DNA. We have shown that retinoic acid inhibits the expression of the transformed phenotype in src-453 cells which express the v-src oncogene. This is indicated by the restoration of contact inhibition and reduction in anchorage-independent growth. In these cells retinoic acid also causes a reduction in the levels of ODC activity. In contrast, retinoic acid stimulates the expression of the transformed phenotype and increases the levels of ODC activity in ras-C2 cells which express v-Ha-ras. These results show that the expression of specific oncogenes can influence the response of cells in vitro to retinoids. Retinoids do not affect the synthesis of the oncogene products pp60src and p21ras. For the pp60src we have shown that retinoic acid does not significantly affect the protein kinase activity and therefore does not appear to act at the level of the kinase. The v-Ha-ras transformed cells produce TGFBeta, which inhibits anchorage-independent growth of these cells. Retinoids appear to reduce the level of active TGFBeta secreted into the medium indicating that the increase in anchorage-independent growth by retinoids is related to reduced levels of TGFBeta. TGFBeta appears to act synergistically with the src-oncogene by enhancing the expression of the transformed phenotype; retinoic acid also inhibits this increase in anchorage-independent growth. We are examining now the levels of TGFBeta-synthesis in these cells and try to identify specific protein(s) that might be affected by TGFBeta and retinoic acid and would be involved in the action of these agents.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Intramural Research (Z01)
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Ueda, Eiichiro; Kurebayashi, Shogo; Sakaue, Morito et al. (2002) High incidence of T-cell lymphomas in mice deficient in the retinoid-related orphan receptor RORgamma. Cancer Res 62:901-9
Kurebayashi, S; Sumitani, S; Kasayama, S et al. (2001) TNF-alpha inhibits 3T3-L1 adipocyte differentiation without downregulating the expression of C/EBPbeta and delta. Endocr J 48:249-53
Jetten, A M; Kurebayashi, S; Ueda, E (2001) The ROR nuclear orphan receptor subfamily: critical regulators of multiple biological processes. Prog Nucleic Acid Res Mol Biol 69:205-47
Kurebayashi, S; Ueda, E; Sakaue, M et al. (2000) Retinoid-related orphan receptor gamma (RORgamma) is essential for lymphoid organogenesis and controls apoptosis during thymopoiesis. Proc Natl Acad Sci U S A 97:10132-7