Tgf-Beta Induces Apoptosis through Smad-Mediated Expression of Dap-Kinase
Resource
NATURE CELL BIOLOGY v.4 n.1 pp.51-58
Journal
NATURE CELL BIOLOGY
Journal Volume
v.4
Journal Issue
n.1
Pages
51-58
Date Issued
2002
Date
2002
Author(s)
CHEN, RUEY-HWA
Abstract
Transforming growth factor-beta (TGF-beta) and TGF-beta- related factors induce apoptosis in a variety of tissues; however, the mechanism underlying this induction is largely unknown. Here, we demonstrate that TGF-beta 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-beta. 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-beta through the action of Smad2, Smad3 and Smad4. Overexpression of DAP-kinase triggers apoptosis in the absence of TGF-beta, whereas inhibition of DAP-kinase activity protects cells from TGF-beta-induced apoptosis, blocks TGF-beta-induced release of cytochrome c from mitochondria and prevents TGF-beta-induced dissipation of the mitochondrial membrane potential. Our findings indicate that DAP- kinase mediates TGF-beta-dependent apoptosis by linking Smads to mitochondrial-based pro-apoptotic events.
Subjects
GROWTH-FACTOR-BETA
PROGRAMMED CELL-DEATH
TRANSFORMING GROWTH -FACTOR-BETA-1
FUNCTIONAL COOPERATION
SIGNALING PATHWAYS
DOWN-REGULATION