TGF-β induces apoptosis through Smad-mediated expression of DAP-kinase

Top Cited Papers
Publisher Website
Google Scholar
Abstract
Transforming growth factor-β (TGF-β) and TGF-β-related factors induce apoptosis in a variety of tissues; however, the mechanism underlying this induction is largely unknown. Here, we demonstrate that TGF-β induces the expression of the death-associated protein kinase (DAP-kinase) as an immediate early response in cells that undergo apoptosis in response to TGF-β. DAP-kinase is a positive mediator of apoptosis induced by certain cytokines and oncogenes. We show that the DAP-kinase promoter is activated by TGF-β through the action of Smad2, Smad3 and Smad4. Overexpression of DAP-kinase triggers apoptosis in the absence of TGF-β, whereas inhibition of DAP-kinase activity protects cells from TGF-β-induced apoptosis, blocks TGF-β-induced release of cytochrome c from mitochondria and prevents TGF-β-induced dissipation of the mitochondrial membrane potential. Our findings indicate that DAP-kinase mediates TGF-β-dependent apoptosis by linking Smads to mitochondrial-based pro-apoptotic events.