TGF-beta induces apoptosis through Smad-mediated expression of DAP-kinase.
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.
Jang
Chuan-Wei
CW
Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
Chen
Chun-Han
CH
Chen
Chun-Chieh
CC
Chen
Jia-yun
JY
Su
Yi-Hsien
YH
Chen
Ruey-Hwa
RH
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000502:physiology*; D064550:Death-Associated Protein Kinases; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D011401:Promoter Regions, Genetic; D015398:Signal Transduction / Q000187:drug effects; D051899:Smad2 Protein; D051900:Smad3 Protein; D051901:Smad4 Protein; D015534:Trans-Activators / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D051017:Apoptosis Regulatory Proteins; D004268:DNA-Binding Proteins; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; C497796:SMAD4 protein, human; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D051901:Smad4 Protein; C490810:Smad4 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D064550:Death-Associated Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases