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TGF-beta induces apoptosis through Smad-mediated expression of DAP-kinase
Chuan-Wei Jang1, Chun-Han Chen, Chun-Chieh Chen
1Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
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.
Insights
Transforming growth factor-beta (TGF-beta) triggers cell death by inducing death-associated protein kinase (DAP-kinase). This protein links Smad signaling to mitochondrial events, mediating TGF-beta-induced apoptosis.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- Transforming growth factor-beta (TGF-beta) is known to induce apoptosis across various tissues.
- The precise molecular mechanisms driving TGF-beta-mediated apoptosis remain largely unelucidated.
Purpose of the Study:
- To investigate the role of death-associated protein kinase (DAP-kinase) in TGF-beta-induced apoptosis.
- To elucidate the signaling pathway linking TGF-beta to apoptotic events.
Main Methods:
- Analysis of DAP-kinase gene expression in response to TGF-beta.
- Reporter assays to assess DAP-kinase promoter activity.
- Smad protein involvement in promoter activation was examined.
- Functional studies involving DAP-kinase overexpression and inhibition.
- Mitochondrial assays to evaluate cytochrome c release and membrane potential.
Main Results:
- TGF-beta rapidly induces DAP-kinase expression as an early response in apoptotic cells.
- Smad2, Smad3, and Smad4 mediate TGF-beta-induced activation of the DAP-kinase promoter.
- DAP-kinase overexpression induces apoptosis independently of TGF-beta.
- Inhibition of DAP-kinase prevents TGF-beta-induced apoptosis, cytochrome c release, and mitochondrial membrane potential dissipation.
Conclusions:
- DAP-kinase acts as a key mediator in TGF-beta-induced apoptosis.
- TGF-beta signaling activates DAP-kinase expression via Smad proteins.
- DAP-kinase links Smad signaling to mitochondrial apoptotic pathways.