RAS and TGF-β exert antagonistic effects on extracellular matrix gene expression and fibroblast transformation

Ras, Raf, and Fos function as components in a signal transduction pathway that is constitutively active in many cancers. Many of the changes that underlie cell transformation arise through changes in gene expression. We have used gene expression pro. ling of 3T3 cells transformed by Ras, Raf, and Fos to de. ne the common and distinct targets of transcriptional control by each of these oncogenes. In this analysis, the most strongly conserved feature of cell transformation at the transcriptional level is the transcriptional repression of genes that encode components of the extracellular matrix (ECM). TGF-beta treatment of fibroblasts is known to increase production of ECM, suggesting that TGF-beta might selectively reverse some of the gene expression changes that occur during cell transformation. Using gene expression pro. ling of the TGF-beta response, we show that the ability of TGF-beta to reverse the changes in gene expression brought about by cellular transformation is essentially confined to genes that encode components of the ECM and the cytoskeleton. This selective reversal of transformation-induced changes in gene expression is associated with partial reversal of many parameters of cell transformation. The results demonstrate a correlation between gene repression by the Ras/Raf/ERK signaling pathway, gene activation by the TGF-beta signaling pathway, and the transformed phenotype in fibroblasts.