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Transformed rat tracheal epithelial cells exhibit alterations in transforming growth factor-beta secretion and
R W Steigerwalt1, J E Rundhaug, P Nettesheim
1Laboratory of Pulmonary Pathobiology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709.
Abstract:
The purpose of our studies was to define abnormalities in the transforming growth factor-beta (TGF-beta) system of transformed rat tracheal epithelial (RTE) cells that might cause their abnormal growth behavior. We found that many, but not all, of the transformed cell lines were hyporesponsive or unresponsive to the growth inhibitory effects of TGF-beta 1. Scatchard and receptor cross-linking analyses indicated that loss of TGF-beta 1 responsiveness of transformed cells was probably not due to changes in receptor number or affinity, or to changes in expression of the three TGF-beta-binding protein subtypes. Transformed cells were found to secrete far less TGF-beta-like activity (less than 1/10) than primary cells. Cultured normal and transformed RTE cells expressed three TGF-beta 1 transcripts of 2.5, 1.9, and 1.4 kb. In contrast, rat kidney tissue, a rat embryo fibroblast cell line, and a rat liver cell line expressed only the typical 2.5-kb mRNA transcript commonly reported in the literature. In spite of the marked differences in TGF-beta secretion between normal and transformed cells, their levels of TGF-beta 1 mRNA expression were similar. This suggests a change in the posttranscriptional regulation of TGF-beta 1 expression. TGF-beta 2 message was not detected in either normal or transformed RTE cells in culture. These findings are consistent with the hypothesis that the abnormal growth behavior of transformed RTE cells is at least in part due to disturbances of the TGF-beta system.
Insights
Transformed rat tracheal epithelial cells show reduced responsiveness to transforming growth factor-beta 1 (TGF-beta 1) due to impaired secretion, not receptor changes. This TGF-beta system disturbance contributes to their abnormal growth.
Area of Science:
- Cell Biology
- Molecular Biology
- Cancer Research
Background:
- The transforming growth factor-beta (TGF-beta) system plays a critical role in regulating cell growth and differentiation.
- Abnormalities in the TGF-beta pathway are implicated in various cancers, including epithelial cancers.
Purpose of the Study:
- To investigate the specific defects in the TGF-beta system of transformed rat tracheal epithelial (RTE) cells that contribute to their aberrant proliferation.
- To determine if altered TGF-beta signaling or expression is responsible for the abnormal growth of transformed RTE cells.
Main Methods:
- Assessed TGF-beta 1 responsiveness in normal and transformed RTE cells.
- Utilized Scatchard and receptor cross-linking analyses to evaluate TGF-beta receptor characteristics.
- Quantified TGF-beta secretion levels and analyzed TGF-beta 1 mRNA expression using various cell lines and tissues.
Main Results:
- Transformed RTE cells exhibited hyporesponsiveness or unresponsiveness to TGF-beta 1's growth inhibitory effects.
- Receptor analysis revealed no significant changes in receptor number, affinity, or binding protein subtypes.
- Transformed cells secreted significantly less TGF-beta activity compared to primary cells, despite similar TGF-beta 1 mRNA levels.
- Unique TGF-beta 1 mRNA transcripts (2.5, 1.9, 1.4 kb) were observed in RTE cells, unlike other tested rat tissues/cells.
Conclusions:
- The abnormal growth of transformed RTE cells is associated with significant disturbances in the TGF-beta system, particularly reduced TGF-beta secretion.
- Posttranscriptional regulation of TGF-beta 1 expression appears altered in transformed RTE cells.
- These findings support the hypothesis that dysregulation of the TGF-beta pathway contributes to the neoplastic behavior of RTE cells.