Negative regulation of gene expression by TGF‐β

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Abstract
Stromelysin gene expression is transcriptionally activated by a number of growth factors (e.g., EGF and PDGF), tumor promoters (e.g., TPA), and oncogenes (e.g., ras, src) through an AP‐1‐dependent mechanism. TGF‐β repression of stromelysin induction is mediated at the level of transcription by an element located at position −709 in the rat stromelysin promoter referred to as the TGF‐β inhibitory element (TIE). A TIE‐binding protein complex is induced by treatment of rat fibroblasts with TGF‐β. This protein complex contains the protooncogene c‐fos, and induction of c‐fos by TGF‐β is required for the repressive effects of TGF‐β on stromelysin gene expression. Interestingly, c‐fos induction is also required for stimulation of stromelysin expression by EGF in rat fibroblasts. Preliminary studies suggest that differential regulation of members of the jun family of early‐response genes may explain this apparent paradox and determine whether stromelysin is induced or repressed by growth factors. TGF‐β stimulation therefore initiates a cascade of events that results in a specific pattern of gene expression: the direct stimulation of early‐response genes can lead to subsequent induction or repression of other genes. Growth factor regulation of matrix metalloproteinases appears to play a role in embryonic development in the morphogenesis of the murine lung. Treatment of embryonic lungs in organ culture with the growth factors EGF or TGF‐β results in stimulation of growth and inhibition of branching morphogenesis. A similar inhibition of branching was observed when these lung rudiments were treated with the matrix metalloproteinase collagenase. Most interestingly, the effects of EGF and TGF‐β can be completely reversed by the tissue inhibitor of metalloproteinases, TIMP. TGF‐β has the opposite effect on growth of murine lung rudiments—growth is inhibited in a dose‐dependent manner. This example illustrates a potential role for growth factor regulation of matrix‐degrading metalloproteinases in complex developmental processes.