Regulation of transforming growth factor beta receptors in H-ras oncogene-transformed rat intestinal epithelial cells.
We have reported that over expression of the H-ras oncogene causes resistance to growth inhibition by transforming growth factor beta 1 (TGF-beta 1) and a time-dependant switch of type II to type I TGF-beta receptor expression in the rat intestinal epithelial cell line IEC-18 (J. Filmus, J. Zhao, and R. N. Buick, Oncogene, 7: 521-526, 1992). Here, we investigate the possible mechanisms involved in H-ras-mediated regulation of TGF-beta receptors in an IEC-18 cell clone expressing H-ras, conditional on the activity of a dexamethasone-sensitive promoter. The switch from type II to type I receptor expression in response to H-ras expression has a requirement for de novo RNA synthesis. In addition, accumulation of TGF-beta receptor type II mRNA is approximately 5-fold lower in ras-expressing cells compared to control cells. Nuclear run-on experiments suggest that the down-regulation of type II receptor mRNA by H-ras oncogene is based, at least in part, on reduced transcription. We have also analyzed the consequences of H-ras expression on the properties of the TGF-beta receptors. Type I and II in IEC-18 cells and type I receptors in ras-transformed cells have similar characteristics in terms of binding affinities for TGF-beta 1 (or TGF-beta 2) turnover rates and glycosylation states. Notably, the type I receptors in ras-transformed cells are not capable of ligand-induced internalization. Although H-ras expression in IEC-18 cells causes resistance to TGF-beta-mediated growth inhibition, the cells remain responsive to TGF-beta 1 stimulation of fibronectin expression. These results are discussed in the context of the knowledge of TGF-beta receptor complexity and signal transduction, and with reference to the potential role for loss of TGF-beta-mediated negative growth regulation in malignant transformation.
Ontario Cancer Institute, University of Toronto, Ontario, Canada.
J
J
Zhao
R N
RN
Buick
D000818:Animals; D002455:Cell Division; D002467:Cell Nucleus / Q000378:metabolism; D002471:Cell Transformation, Neoplastic; D015536:Down-Regulation; D005353:Fibronectins / Q000378:metabolism; D011905:Genes, ras; D006031:Glycosylation; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000473:pathology*; D008024:Ligands; D011485:Protein Binding; D016283:Proto-Oncogene Proteins p21(ras) / Q000502:physiology*; D012334:RNA, Neoplasm / Q000378:metabolism; D051381:Rats; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D005353:Fibronectins; D008024:Ligands; D012334:RNA, Neoplasm; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D016283:Proto-Oncogene Proteins p21(ras)