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11 Growth Control by TGF-β: Mechanisms Controlling Cell Cycle Progression and Apoptosis

Peter M. Siegel, Joan Massagué


It has been more than 25 years since the activity of the transforming growth factors was first described in acid/ethanol extracts of both sarcoma- and carcinoma-derived cell lines (Roberts et al. 1980). Although the ability of these soluble factors to stimulate growth of normal rat kidney cells in soft agar accounts for their designation as “transforming” factors, the subsequent purification of TGF-β from these crude extracts revealed that it elicited strong antiproliferative responses (Roberts et al. 1985). Soon thereafter, it was appreciated that TGF-β and many of its family members are in fact multifunctional cytokines capable of influencing diverse biological processes ranging from cell proliferation, apoptosis, differentiation, migration, and modulation of the cell microenvironment through production of extracellular matrix components. However, the antiproliferative effect of TGF-β has remained as one of its most paradigmatic actions and the focus of much work. This chapter focuses on the nature of this response in various cell types and the manner in which TGF-β may induce another growth-limiting response—namely, apoptosis. Mechanisms leading to the abrogation of TGF-β-mediated growth control are also discussed.

The proper balance between cell proliferation and apoptosis is central to physiological tissue growth and homeostasis. Perturbations of this balance, such as increased cellular proliferation or decreased apoptosis, can lead to development of pathological conditions such as hyperplasia and eventually cancer. Conversely, reduced proliferation or elevated cell death can result in the loss of specific cell populations leading to the development of degenerative diseases. Members of the TGF-β family...

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