Department of Cell Biology , Vanderbilt University , Nashville , Tennessee .
Mol Reprod Dev 32 : 111-20 ( 1992)
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-beta 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-beta inhibitory element ( TIE ) .
A TIE-binding protein complex is induced by treatment of rat fibroblasts with TGF-beta .
This protein complex contains the protooncogene c-fos , and induction of c-fos by TGF-beta is required for the repressive effects of TGF-beta 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-beta 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-alpha 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-alpha can be completely reversed by the tissue inhibitor of metalloproteinases , TIMP .
TGF-beta 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 .
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Department of Biochemistry and Molecular Biology , Texas Tech University Health Sciences Center , Lubbock 79430 .
Mol Cell Endocrinol 84 : 109-18 ( 1992)
Abstract
Replicative DNA synthesis , as measured by thymidine incorporation , has been measured in rat uterine cells in primary culture in response to growth factors .
Insulin , insulin-like growth factor-I ( IGF-I ) , multiplication-stimulating activity ( MSA ) and platelet-derived growth factor ( PDGF ) stimulated DNA synthesis , while estradiol , epidermal growth factor ( EGF ) , transforming growth factor-beta ( TGF-beta ) , basic fibroblast growth factor ( bFGF ) and relaxin did not stimulate or did so weakly and only at very high concentrations .
Uterine acid extracts also stimulated DNA synthesis .
IGF-I stimulated at concentrations consistent with its acting through the IGF-I receptor ; however , insulin stimulated at concentrations higher than expected for its acting through its receptor and this its action may be mediated through the IGF-I receptor .
IGF-I was found in uterine tissue by radioimmunoassay ( RIA ) .
There was a 5- to 10-fold increase in IGF-I in the uteri from ovariectomized rats that had been treated with estradiol 24 h earlier .
This is analogous to the increase in growth factor activity found previously in rat uterus after 24-h estradiol treatment ( Beck , C.A. and Garner , C.W. ( 1989 ) Mol .
Cell .
Endocrinol .
63 , 93-101 ) .
These data are consistent with the hypothesis that estradiol effects in the uterus are in part mediated through IGF-I .