Ha-ras oncogene transformation abolishes retinoic acid-induced reduction of intracellular fibronectin.
All-trans-retinoic acid (RA) is a master regulator of cell differentiation and in this process it greatly influences cell adhesion and the elaboration of the extracellular matrix. Therefore, we were interested in the effect of RA on the biosynthesis of fibronectin (FN). RA reduced the level of intracellular FN in a time- and concentration-dependent fashion in NIH-3T3 cells, but not in NIH-3T3 cells transformed by an activated Ha-ras oncogene. Since the steady-state level of FN transcripts did not change after treatment of the cells with RA for various times or concentrations, RA probably acts at the translational level. In NIH-3T3 cells, RA had distinct effects on different receptors, from decreasing retinoic acid receptor (RAR)alpha to increasing RAR beta expression to no effect on RAR gamma. Transformation of NIH-3T3 cells with an activated Ha-ras oncogene downmodulated RAR expression and also abolished responsiveness to RA. A variety of approaches permitted the following conclusions: 1) RA-dependent FN downmodulation is mediated by RARs, 2) retinoid X receptors (RXRs) mediate the observed reduction of RAR alpha by RA, and 3) the blockade of RA responsiveness by Ha-ras-transfected cells cannot be overcome by overexpression of RAR alpha. These studies have identified fibronectin and RAR alpha as RA targets in fibroblast cells and have shown that oncogenic transformation renders the cells resistant to RA action.
De-Luca
L M
LM
Laboratory of Cellular Carcinogenesis and Tumor Promotion, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA.
Scita
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D005353:Fibronectins / Q000502:physiology*; D005786:Gene Expression Regulation; D011905:Genes, ras / Q000502:physiology*; D006801:Humans; D007425:Intracellular Membranes; D016283:Proto-Oncogene Proteins p21(ras) / Q000502:physiology*; D014212:Tretinoin / Q000502:physiology*
D005353:Fibronectins; D014212:Tretinoin; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)