During lung development, cell proliferation and differentiation are closely coordinated with programmed cell death (apoptosis). The mechnisms by which cells initiate and execute an intracellular programthat leads to cell death are the subject of extensive sudies. Two families of intracellular proteins have been implicated in apoptotic signaling, i.e. Bcl-2-like proteins and ICE-like proteases, recently renamed caspases. Two families of secreted polypeptides induce receptor-mediated programmed cell death: the TNF-family and the TGF-beta superfamily, for which TGF-beta is considered as the prrototype. In contrast to TNF-mediated celldeath, TGF-beta and related factors are though to be major inducers of developmental apoptosis in non-hematopoietic tissues and organs. Yet, whereas rapid progress is made on the characterization of TNF-receptor-mediated signaling that leads to cell death, the mechanisms of programmed cell death following activiation of TGF-beta receptors are unknown. Recent progress on the mechanism of signaling by TGF-beta and related factors has led to the identification and characterization of their receptors as transmembrane serine/threonine kinases and the Smads as intracellular effectors of receptor signaling, which following nuclear translocationare though to function as transcription factors. Inthis grant appliction, we propose to characterize the mechanisms by which receptor activation by TGF-beta leads to programmed cell death in vitro. These studies should provide insight into the mechanisms of apoptosis during lung development and following lung injury. Our proposed studies have been subdivided into four Aims.
In Aim 1, we will characterize the role of the type II and type I TGF-beta receptors and the Smads in TGF-beta mediated apoptosis, whereas Aims 2 and 3 focus on the roles of the Bcl-2-like proteins and the caspases, respectively. Finally, in Aim 4, we will study the possible involvement of several cytoplasmic kinases, which recently have been implicated inligand-induced cell death, in TGF-beta-included programmed cell death. Taken together, these studies should allow us to characterize the mechanisms whereby TGF-beta receptor activation signals programmed cell death. Furthrmore, the elucidation of this as yet uncharacterized signaling pathway shouls provide a paradigm for the cell death induced by the other TGF-beta relted factors in this superfamily. Finally, our findings are likely to provide insight into the role of different classes of signaling mediators in apoptosis in the lung.
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