Cellular mechanisms of TGF-beta action.
Transforming growth factor beta (TGF-beta), initially identified in platelet extracts by virtue of its ability to confer anchorage-independent growth and a neoplastic phenotype on mesenchymal cells, has subsequently been identified as a potent inhibitor of proliferation in most cells of epithelial origin. Our laboratory has investigated the role of specific second messengers in mediating the transcriptional responses of fibroblasts following addition of TGF-beta 1. Our studies indicate that TGF-beta 1, alone and in conjunction with epidermal growth factor (EGF), is capable of stimulating increases in both phosphoinositide metabolism and calcium influx, leading to significant increases in intracellular levels of Ca++ and inositol trisphosphate (IP3). Our data indicated that Ca++ influx and inositol phosphate release are coupled in Rat-1 cells, and suggested that influx of Ca++ from the extracellular medium is required for the change in IP3 accumulation observed in response to both EGF and TGF-beta 1. Using nuclear run-on analysis of the transcription of rat transin, a secreted metalloproteinase homologous to human stromelysin, we have also demonstrated a significant inhibition of transin transcription within 10 min of TGF-beta 1 treatment. The ability of TGF-beta 1 to inhibit transin gene transcription was not related to the TGF-beta 1-induced influx of Ca++ or to an increase in intracellular inositol phosphates, since inhibiting production of these second messengers failed to inhibit repression of the transin gene.
Rodland
K D
KD
Department of Cell Biology and Anatomy, Oregon Health Sciences University, Portland 97201-3098.
Muldoon
L L
LL
Magun
B E
BE
D000818:Animals; D002118:Calcium / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005110:Extracellular Space / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism*; D005786:Gene Expression Regulation; D007295:Inositol Phosphates / Q000378:metabolism; D007425:Intracellular Membranes / Q000378:metabolism; D019278:Matrix Metalloproteinase 3; D008666:Metalloendopeptidases / Q000235:genetics; D015290:Second Messenger Systems; D015398:Signal Transduction; D015291:Transforming Growth Factors / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D014945:Wound Healing
D007295:Inositol Phosphates; D004815:Epidermal Growth Factor; D015291:Transforming Growth Factors; D008666:Metalloendopeptidases; D019278:Matrix Metalloproteinase 3; D002118:Calcium