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Transforming growth factor-beta signal transduction in epithelial cells
1Department of Pharmacology, MC H078, Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA 17033, USA.
Abstract:
Transforming growth factor (TGF)-beta is a natural and potent growth inhibitor of a variety of cell types, including epithelial, endothelial, and hematopoietic cells. The ability of TGF-beta to potently inhibit the growth of many solid tumors of epithelial origin, including breast and colon carcinomas, is of particular interest. However, many solid tumor cells become refractory to the growth inhibitory effects of TGF-beta due to defects in TGF-beta signaling pathways. In addition, TGF-beta may stimulate the invasiveness of tumor cells via the paracrine effects of TGF-beta. Accordingly, in order to develop more effective anticancer therapeutics, it is necessary to determine the TGF-beta signal transduction pathways underlying the growth inhibitory effects and other cellular effects of TGF-beta in normal epithelial cells. Thus far, two primary signaling cascades downstream of the TGF-beta receptors have been elucidated, the Sma and mothers against decapentaplegic homologues and the Ras/mitogen-activated protein kinase pathways. The major objective of this review is to summarize TGF-beta signaling in epithelial cells, focusing on recent advances involving the Sma and mothers against decapentaplegic homologues and Ras/mitogen-activated protein kinase pathways. This review is particularly timely in that it provides a comprehensive summary of both signal transduction mechanisms and the cell cycle effects of TGF-beta.
Insights
Transforming growth factor-beta (TGF-beta) inhibits normal cell growth but can be bypassed by tumors. Understanding TGF-beta signaling in epithelial cells is crucial for developing new cancer therapies.
Area of Science:
- Cell Biology
- Molecular Biology
- Oncology
Background:
- Transforming growth factor-beta (TGF-beta) is a potent inhibitor of normal cell growth, including epithelial cells.
- TGF-beta's growth inhibitory effects are relevant to epithelial-derived tumors like breast and colon carcinomas.
- Tumor cells often develop resistance to TGF-beta due to signaling pathway defects, and TGF-beta may promote tumor invasiveness.
Purpose of the Study:
- To review the TGF-beta signal transduction pathways in epithelial cells.
- To focus on recent advances in the Smad and Ras/MAPK pathways downstream of TGF-beta receptors.
- To summarize TGF-beta's signal transduction mechanisms and cell cycle effects.
Main Methods:
- Literature review of TGF-beta signaling pathways.
- Focus on Smad and Ras/MAPK signaling cascades.
- Analysis of TGF-beta's effects on cell cycle regulation.
Main Results:
- Two primary TGF-beta signaling cascades identified: Smad and Ras/MAPK pathways.
- These pathways mediate TGF-beta's diverse cellular effects.
- Understanding these pathways is key to overcoming tumor resistance.
Conclusions:
- TGF-beta signaling pathways, particularly Smad and Ras/MAPK, are critical in normal epithelial cells.
- Elucidating these pathways is essential for developing targeted anticancer therapeutics.
- This review provides a comprehensive summary of TGF-beta signaling and its cell cycle effects.