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

Nat Cell Biol. 2002 Jan;4(1):51-8. doi: 10.1038/ncb731.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Apoptosis / physiology*
  • Apoptosis Regulatory Proteins
  • Calcium-Calmodulin-Dependent Protein Kinases / genetics
  • Calcium-Calmodulin-Dependent Protein Kinases / physiology*
  • DNA-Binding Proteins / physiology*
  • Death-Associated Protein Kinases
  • Enzyme Activation / drug effects
  • Enzyme Activation / genetics
  • Humans
  • Mice
  • Mitochondria / drug effects
  • Mitochondria / physiology
  • Promoter Regions, Genetic
  • Signal Transduction / drug effects
  • Smad2 Protein
  • Smad3 Protein
  • Smad4 Protein
  • Trans-Activators / physiology*
  • Transforming Growth Factor beta / pharmacology*
  • Tumor Cells, Cultured


  • Apoptosis Regulatory Proteins
  • DNA-Binding Proteins
  • SMAD2 protein, human
  • SMAD3 protein, human
  • SMAD4 protein, human
  • Smad2 Protein
  • Smad2 protein, mouse
  • Smad3 Protein
  • Smad3 protein, mouse
  • Smad4 Protein
  • Smad4 protein, mouse
  • Trans-Activators
  • Transforming Growth Factor beta
  • Death-Associated Protein Kinases
  • Calcium-Calmodulin-Dependent Protein Kinases