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

Nature Cell Biology volume 4, pages 51–58 (2002)Cite this article

An Erratum to this article was published on 01 April 2002

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.

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Figure 1: Upregulation of DAP-kinase during TGF-β-induced apoptosis.
Figure 2: TGF-β regulates DAP-kinase promoter activity but not mRNA stability.
Figure 3: TGF-β-induced DAP-kinase transcription requires Smad2, Smad3 and Smad4.
Figure 4: Smad-binding elements are required for DAP-kinase induction by TGF-β.
Figure 5: DAP-kinase expression induces apoptosis and sensitizes cells to TGF-β-dependent apoptosis.
Figure 6: Expression of DAP-kinase dominant negative mutants protect Hep3B cells from TGF-β-induced apoptosis.
Figure 7: Antisense inhibition of DAP-kinase expression specifically prevents TGF-β-induced apoptosis.
Figure 8: Dominant negative DAP-kinase protects cells from mitochondrial damage induced by TGF-β.

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Acknowledgements

We thank R. Derynck, X.-H. Feng, M. Kawabata, A. Nakao and C.-H. Heldin for various Smad constructs, Smad adenoviruses and Smad null cells, and B. Vogelstein for recombinant adenovirus vector systems. We also thank R. Derynck for critical reading of the manuscript, K. Peck and C.-H. Tsai for instructions on microarray analysis, C.-N. Tsai for advice on the recombinant adenovirus construction and G. Lin for his help in the initial phase of this research. This work was supported by National Science Council Frontier Grant 90-2321-B-002-004 to R.-H.C.

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  1. Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei, 100, Taiwan

    Chuan-Wei Jang, Chun-Hau Chen, Chun-Chieh Chen, Jia-yun Chen, Yi-Hsien Su & Ruey-Hwa Chen

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Correspondence to Ruey-Hwa Chen.

Supplementary information

Table S1

List of genes whose expression was not altered by TGF- treatment of Hep3B cells. (PDF 68 kb)

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Jang, CW., Chen, CH., Chen, CC. et al. TGF-β induces apoptosis through Smad-mediated expression of DAP-kinase. Nat Cell Biol 4, 51–58 (2002). https://doi.org/10.1038/ncb731

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