TGF-β-dependent Cell Growth Arrest and Apoptosis

Transforming growth factor beta (TGF-β) is a member of a large family of multifunctional secreted polypeptides that are potent regulators of cell growth, differentiation, and matrix production (Massague, 1998; Dijke et al., 2000;Derynck et al., 2001).TGF-β was initially identified and named on the basis of its ability to stimulate fibroblast growth in soft agar, but it is now the best-studied growth inhibitory protein.Its molecular components at each step in the TGF-β signaling pathway have been identified as tumor suppressors (Massague, 1998).Over the last two decades, the TGF-β family has emerged as a major source of signals that control cell growth and differentiation (Massague et al., 2000).Members of the TGFβ family produce different effects, depending on the type and state of the cell.The signals of TGF-β family members are transduced across the plasma membrane by the heteromeric interaction of two receptors, types I and II, which are serine/ threonine kinases.The initiation of the signaling requires binding of TGF-β to the TGF-β type II receptor, a constitutively active serine/threonine kinase, which subsequently transphosphorylates the TGF-β type I receptor.The activated type I receptor initiates intracellular signaling through the activation of specific Smad proteins.Smads relay signals into the nucleus where they, together with other proteins, direct transcriptional responses (Massague, 2000).In this review, we will focus on how TGF-β mediates cell growth arrest and apoptosis.