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Cytoprotective membrane-permeable peptides designed from the Bax-binding domain of Ku70

Nature Cell Biology volume 5, pages 352–357 (2003)Cite this article

Abstract

Bax is a pro-apoptotic member of Bcl-2 family proteins and is central to mitochondria-dependent apoptosis1,2,3. Bax resides in the cytosol as a quiescent protein and translocates into mitochondria after apoptotic stimuli4. Ku70 is a 70K subunit of the Ku complex, which has an important role in DNA double-strand break (DSB) repair in the nucleus5. In another article in this issue, we reported that Ku70 interacts with pro-apoptotic protein Bax in the cytosol and prevents its mitochondrial translocation6, suggesting that Ku70 suppresses Bax-mediated apoptosis. Here, we describe the development of a new membrane-permeable peptide, Bax-inhibiting peptide (BIP) that inhibits Bax-mediated apoptosis, on the basis of the previous finding that showed an interaction between Ku70 and Bax. BIP is comprised of five amino acids designed from the Bax-binding domain of Ku70, and suppresses the mitochondrial translocation of Bax. BIP inhibited Bax-mediated apoptosis induced by staurosporine, UVC irradiation and anti-cancer drugs in several types of cells. BIP may provide valuable information in the development of therapeutics that control apoptosis-related diseases.

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Figure 1: New peptides designed from Ku70 show anti-Bax activity.
Figure 2: Inhibitory effects of BIP against various apoptotic stimuli.
Figure 3: BIP inhibits the mitochondrial translocation of Bax.
Figure 4: BIP binds Bax in vivo.
Figure 5: Ku70-derived peptides bind Bax and dissociate Ku70 from Bax.

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References

  1. Green, D.R. & Reed, J.C. Mitochondria and apoptosis. Science 281, 1309–1312 (1998).

    Article  CAS  Google Scholar 

  2. Gross, A., McDonnell, J.M. & Korsmeyer, S.J. BCL-2 family members and the mitochondria in apoptosis. Genes Dev 13, 1899–1911 (1999).

    Article  CAS  Google Scholar 

  3. Wei, M.C. et al. Pro-apoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death. Science 292, 727–730 (2001).

    Article  CAS  Google Scholar 

  4. Wolter, K.G. et al. Movement of Bax from the cytosol to mitochondria during apoptosis. J. Cell Biol. 139, 1281–1292 (1997).

    Article  CAS  Google Scholar 

  5. Walker, J.R., Corpina, R.A. & Goldberg, J. Structure of the Ku heterodimer bound to DNA and its implications for double-strand break repair. Nature 412, 607–614 (2001).

    Article  CAS  Google Scholar 

  6. Sawada, M. et al. Ku70 suppresses the apoptotic translocation of Bax to mitochondria. Nature Cell Biol. 5, 320–329 (2003).

    Article  CAS  Google Scholar 

  7. Zhang, Z. et al. The three-dimensional structure of the C-terminal DNA-binding domain of human Ku70. J. Biol. Chem. 276, 38231–38236 (2001).

    CAS  Google Scholar 

  8. Ashkenazi, A. & Dixit, V.M. Death receptors: signaling and modulation. Science 281, 1305–1308 (1998).

    Article  CAS  Google Scholar 

  9. Matsuyama, S., Llopis, J., Deveraux, Q.L., Tsien, R.Y. & Reed, J.C. Changes in intramitochondrial and cytosolic pH: early events that modulate caspase activation during apoptosis. Nature Cell Biol. 2, 318–325 (2000).

    Article  CAS  Google Scholar 

  10. Suzuki, M., Youle, R.J. & Tjandra, N. Structure of Bax: coregulation of dimer formation and intracellular localization. Cell 103, 645–654 (2000).

    Article  CAS  Google Scholar 

  11. Hsu, Y.T. & Youle, R.J. Bax in murine thymus is a soluble monomeric protein that displays differential detergent-induced conformations. J. Biol. Chem. 273, 10777–10783 (1998).

    Article  CAS  Google Scholar 

  12. Nechushtan, A., Smith, C.L., Hsu, Y.T. & Youle, R.J. Conformation of the Bax C-terminus regulates subcellular location and cell death. EMBO J. 18, 2330–2341 (1999).

    Article  CAS  Google Scholar 

  13. Vila, M. et al. Bax ablation prevents dopaminergic neurodegeneration in the 1-methyl- 4- phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease. Proc. Natl Acad. Sci. USA 98, 2837–2842 (2001).

    Article  CAS  Google Scholar 

  14. Selznick, L.A., Zheng, T.S., Flavell, R.A., Rakic, P. & Roth, K.A. Amyloid β-induced neuronal death is bax-dependent but caspase-independent. J. Neuropathol. Exp. Neurol. 59, 271–279 (2000).

    Article  CAS  Google Scholar 

  15. Korsmeyer, S.J. BCL-2 gene family and the regulation of programmed cell death. Cancer Res. 59, 1693s–1700s (1999).

    CAS  PubMed  Google Scholar 

  16. Matsuyama, S., Schendel, S.L., Xie, Z. & Reed, J.C. Cytoprotection by Bcl-2 requires the pore-forming α5 and α6 helices. J. Biol. Chem. 273, 30995–31001 (1998).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank D.A. Boothman for critical reviewing of the manuscript and encouragement. This work was supported in part by the Blood Center Research Foundation, Northwest Mutual Foundation, American Society of Hematology (Junior Faculty Award) to S.M.

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Authors and Affiliations

  1. The Blood Center of South Eastern Wisconsin and Department of Biochemistry, Blood Research Institute, Medical College of Wisconsin 8727, Watertown Plank Rd, Milwaukee, 53226, WI

    Motoshi Sawada, Paulette Hayes & Shigemi Matsuyama

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  1. Motoshi Sawada
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Correspondence to Shigemi Matsuyama.

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Supplementary information

Supplementary Figures

Figure S1 Flow cytometric propidium iodide (PI) exclusion analysis. (PPT 402 kb)

Figure S2 Inhibitory effects of BIP against various apoptotic stimuli.

Figure S3 Optimization of Bax-plasmid transfection into Du145 cells.

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Sawada, M., Hayes, P. & Matsuyama, S. Cytoprotective membrane-permeable peptides designed from the Bax-binding domain of Ku70. Nat Cell Biol 5, 352–357 (2003). https://doi.org/10.1038/ncb955

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