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Co-involvement of the mitochondria and endoplasmic reticulum in cell death induced by the novel ertargeted protein HAP

Abstract

HAP (a homologue of the ASY/Nogo-B protein), a novel human apoptosis-inducing protein, was found to be identical to RTN3. In an earlier study, we demonstrated that HAP localized exclusively to the endoplasmic reticulum (ER) and that its overexpression could induce cell apoptosis via a depletion of endoplasmic reticulum (ER) Ca2+ stores. In this study, we show that overexpression of HAP causes the activation of caspase-12 and caspase-3. We still detected the collapse of mitochondrial membrane potential (Δωm) and the release of cytochrome c in HAP-overexpressing HeLa cells. All the results indicate that both the mitochondria and the ER are involved in apoptosis caused by HAP overexpression, and suggest that HAP overexpression may initiate an ER overload response (EOR) and bring about the downstream apoptotic events.

References

  1. 1.

    Li, Q., Qi, B., Oka, K. and Shimakage, M. Link of a new type of apoptosis-inducing gene ASY/Nogo-B to human cancer. Oncogene 20 (2001) 3929–3936

    PubMed  CAS  Article  Google Scholar 

  2. 2.

    Qi, B. and Qi, Y.P. Sci. China (Series C). 43 (2000) 310–320.

    CAS  Article  Google Scholar 

  3. 3.

    Qu, X.L., Qi, Y.P. and Qi, B. Generation of multiple mRNA transcripts from the novel human apoptosis-inducing gene hap by alternative polyadenylation utilization and the translational activation function of 3′ untranslated region. Arch. Biochem. Biophys. 400 (2002) 233–244.

    PubMed  CAS  Article  Google Scholar 

  4. 4.

    Qi, B., Qi, Y.P., Liu, Q.Z. and Qu, X.L. A new type of apoptosis inducing gene Chin. Sci. Bull. 46 (2001) 1409–1411.

    Article  Google Scholar 

  5. 5.

    Sambrook, J.F. The involvement of calcium in transport of secretory proteins from the endoplasmic reticulum. Cell 61 (1990) 197–199.

    PubMed  CAS  Article  Google Scholar 

  6. 6.

    Pinton, P., Ferrari D., Rapizzi, E., Di Virgilio, F.D., Pozzan, T. and Rizzuto, R. The Ca2+ concentration of the endoplasmic reticulum is a key determinant of ceramide-induced apoptosis: significance for the molecular mechanism of Bcl-2 action. EMBO J. 20 (2001) 2690–2701.

    PubMed  CAS  Article  Google Scholar 

  7. 7.

    Tagliarino, C., Pink, J.J., Dubyak, G.R., Nieminen, A.L. and Boothman, D.A. Calcium is a key signaling moleculae in β-lapachone-mediated cell death. J. Biol. Chem. 276 (2001) 19150–19159.

    PubMed  CAS  Article  Google Scholar 

  8. 8.

    Jayadev, S., Barrett, J.C. and Murphy, E. Elevated ceramide is downstream of altered calcium homeostasis in low serum-induced apoptosis. AJP-Cell Physiol. 279 (2000) 1640–1647.

    Google Scholar 

  9. 9.

    Nakamura, K., Bossy-Wetzel, E., Burns, K., Fadel, M.P., Lozyk, M., Goping, I.S., Opas, M. and Bleackley, R. Endoplasmic Reticulum Luminal Environment Affect Cell Sensitivity to Apoptosis. J. Cell Biol. 150 (2000) 731–740.

    PubMed  CAS  Article  Google Scholar 

  10. 10.

    Zamzami, N. and Kroemer, G. Mitochondria in apoptosis. How Pandora’s box opens. Nat. Rev. Mol. Cell. Biol. 2 (2001) 67–71.

    PubMed  CAS  Article  Google Scholar 

  11. 11.

    Ferri, K.F. and Kroemer, G. Mitochondria-the suicide organelles. Bioessays 23 (2001) 111–115.

    PubMed  CAS  Article  Google Scholar 

  12. 12.

    Lamkanfi, M., Kalai, M and Vandenabeele. P. Caspase-12: an overview. Cell Death Differ. 11 (2004) 65–368.

    Article  CAS  Google Scholar 

  13. 13.

    Obeng, E. A. and Boise, L. H. Caspase-12 and caspase-4 are not required for caspase-dependent endoplasmic reticulum stress-induced apoptosis. J. Biol. Chem. 280 (2005) 19150–19159.

    Article  CAS  Google Scholar 

  14. 14.

    Kaufman, R. Stress signaling from the lumen of the endoplasmic reticulum Coordination of gene transcriptional and translational controls. Genes (1999) 1211–1233.

  15. 15.

    Adrain, C. and Martin, S.J. The mitochondrial apoptosome: a killer unleashed by the cytochrome seas Trends Biochem. Sci. 26 (2001) 390–397.

    PubMed  CAS  Article  Google Scholar 

  16. 16.

    Nuñez, G., Benedict, M.A., Hu, Y. and Inohara, N. Caspases: the proteases of the apoptotic pathway. Oncogene 17 (1998) 3237–3245.

    PubMed  Article  Google Scholar 

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Correspondence to Yi-Peng Qi.

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Xu, H., Zhou, Q., Liu, X. et al. Co-involvement of the mitochondria and endoplasmic reticulum in cell death induced by the novel ertargeted protein HAP. Cell. Mol. Biol. Lett. 11, 249–255 (2006). https://doi.org/10.2478/s11658-006-0019-1

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Key words

  • Apoptosis-inducing protein HAP
  • Mitochondria
  • Endoplasmic reticulum (ER)
  • Caspase-12
  • Caspase-3
  • Mitochondrial membrane potential (Δωm)
  • Cytochrome c