Analysis of TGF-Inducible Apoptosis

Transforming growth factor-β (TGF-β) is an important regulator of cellular growth and immune homeostasis (1 –3 ). TGFβ is a homodimeric 25-kDa protein which activates cellular signaling through the recruitment and transphos-phorylation of specific heterodimeric cell-surface receptors (4 ). Although activation of TGF-β receptors initiates serine/threonine kinase activity, the subsequent signaling mechanisms involved in a wide array of diverse functional consequences is currently under investigation. TGF-β has been postulated to play important roles in tissue fibrosis and the regulation of the extracellular matrix (5 ), growth arrest of epithelial cells (6 ), regulation of the immune response, and induction of apoptotic cell death (7 –11 ). The essential nature of this cytokine is exemplified by the lethal and nonoverlapping phenotypes of the three highly homologous mammalian TGF-β isoforms, each of which exhibit cell-specific expression (3 ,12 ). TGF-β1 deficient mice exhibit extensive lymphocytic hyperproliferation and the production of autoimmune antibodies found in several human diseases (3 ,13 –16 ).