Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

Mitochondrial pro-apoptotic ARTS protein is lost in the majority of acute lymphoblastic leukemia patients

Oncogene volume 23, pages 5468–5475 (2004)Cite this article

An Erratum to this article was published on 16 December 2004

Abstract

Acquired resistance towards apoptosis is the hallmark of most if not all types of cancer. We have previously identified and characterized ARTS, a broadly expressed protein localized to mitochondria. ARTS was initially shown to mediate TGF-β induced apoptosis. Recently, we have found that high levels of ARTS induce apoptosis without additional pro-apoptotic stimuli. Further, ARTS promotes apoptosis in response to a wide variety of pro-apoptotic stimuli. Here, we report that the expression of ARTS is lost in all lymphoblasts of more than 70% of childhood acute lymphoblastic leukemia (ALL) patients. The loss of ARTS is specific, as the related non-apoptotic protein H5, bearing 83% identity to ARTS, is unaffected. During remission, ARTS expression is detected again in almost all patients. Two leukemic cell lines, ALL-1 and HL-60 lacking ARTS, were resistant to apoptotic induction by ara-C. Transfection of ARTS into these cells restored their ability to undergo apoptosis in response to this chemotherapeutic agent. We found that methylation process contributes to the loss of ARTS expression. We conclude that the loss of ARTS may provide a selective advantage for cells to escape apoptosis thereby contributing to their transformation to malignant lymphoblasts. We therefore propose that ARTS can function as a tumor suppressor protein in childhood ALL.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  • Attardi LD and Jacks T . (1999). Cell Mol. Life Sci., 55, 48–63.

  • Corral J, Lavenir I, Impey H, Warren AJ, Forster A, Larson TA, Bell S, McKenzie AN, King G and Rabbitts TH . (1996). Cell, 85, 853–861.

  • Domen J . (2000). Immunol. Res., 22, 83–94.

  • Eden A, Gaudet F, Waghmare A and Jaenisch R . (2003). Science, 300, 455.

  • Erikson J, Griffin CA, ar-Rushdi A, Valtieri M, Hoxie J, Finan J, Emanuel BS, Rovera G, Nowell PC and Croce CM . (1986). Proc. Nat. Acad. Sci. USA, 83, 1807–1811.

  • Evan GI and Vousden KH . (2001). Nature, 411, 342–348.

  • Field CM and Kellogg D . (1999). Trends Cell Biol., 10, 387–394.

  • Gaudet F, Hodgson JG, Eden A, Jackson-Grusby L, Dausman J, Gray JW, Leonhardt H and Jaenisch R . (2003). Science, 300, 489–492.

  • Gottfried Y, Rotem A, Lotan R, Steller H and Larisch S . (2004). EMBO J., 23 (7), 1627–1635.

  • Green DR and Evan GI . (2002). Cancer Cell, 1, 19–30.

  • Greaves M . (2002). BMJ, 324, 283–287.

  • Hanahan D and Weinberg RA . (2000). Cell, 100, 57–70.

  • Hetts SW . (1998). JAMA, 279, 300–307.

  • Hengartner MO . (2000). Nature, 407, 770–776.

  • Igney FH and Krammer PH . (2002). Nat. Rev. Cancer, 2, 277–288.

  • Jain PK . (2003). Ann. NY Acad. Sci., 983, 71–83.

  • Jones PA . (1999). Trends Genet., 15, 34–37.

  • Kalikin LM, Sims HL and Petty EM . (2000). Genomics, 63, 165–172.

  • Karpf AR and Jones DA . (2002). Oncogene, 21, 5496–5503.

  • Kartmann B and Roth D . (2001). J. Cell Sci., 1114, 839–844.

  • Kinoshita M, Field CM, Coughlin ML, Straight AF and Mitchison TJ . (2002). Dev. Cell, 6, 791–802.

  • Larisch S, Yi Y, Lotan R, Kerner H, Eimerl S, Tony Parks W, Gottfried Y, Birkey Reffey S, de Caestecker MP, Danielpour D, Book-Melamed N, Timberg R, Duckett CS, Lechleider RJ, Steller H, Orly J, Kim SJ and Roberts AB . (2000). Nature Cell Biol., 2, 915–921.

  • Malfoy B . (2000). J. Cell Sci., 113, 3887–3888.

  • Meier P, Finch A and Evan G . (2000). Nature, 407, 796–801.

  • Megonigal MD, Rappaport EF, Jones DH, Williams TM, Lovett BD, Kelly KM, Lerou PH, Moulton T, Budarf ML and Felix CA . (1998). Proc. Nat. Acad. Sci. USA, 95, 6413–6418.

  • McKenna SL and Cotter TG . (1997). Adv. Cancer Res., 71, 121–164.

  • Osaka M, Rowley JD and Zeleznik-Le NJ . (1999). Proc. Natl. Acad. Sci. USA, 96, 6428–6433.

  • Pui CH . (1995). N. Engl. J. Med., 332, 1618–1630.

  • Rinkenberger JL and Korsmeyer SJ . (1997). Curr. Opin. Genet. Dev., 7, 589–596.

  • Rountree MR, Bachman KE, Herman JG and Baylin SB . (2001). Oncogene, 20, 3156–3165.

  • Rubnitz JE and Pui CH . (2003). Cancer Treat. Rev., 29, 31–44.

  • Shurtleff SA, Buijs A, Behm FG, Rubnitz JE, Raimondi SC, Hancock ML, Chan GC, Pui CH, Grosveld G and Downing JR . (1995). Leukemia, 9, 1985–1989.

  • Soengas MS, Capodieci P, Polsky D, Mora J, Esteller M, Opitz-Araya X, McCombie R, Herman JG, Gerald WL, Lazebnik YA, Cordon-Cardo C and Lowe SW . (2001). Nature, 409, 207–211.

  • Thompson CB . (1995). Science, 267, 1456–1462.

  • Vaux DL and Korsmeyer SJ . (1999). Cell, 96, 245–254.

  • Zagonel V, Lo Re G, Marotta G, Babare R, Sardeo G, Gattei V, De Angelis V, Monfardini S and Pinto A . (1993). Leukemia, 1, 30–35.

Download references

Acknowledgements

We wish to thank Hermann Steller for his help throughout this work and for thoughtful reading of the manuscript. We also thank Ziva Weissman for excellent technical assistance, Zvi Ben-Ishai from Rambam Medical Center, Haifa, Israel for his continuous support, David Barzilai and the Erna D Leir Foundation for Research of Degenerative Brain Diseases for their generous support. This work was supported by a grant from the Israel Cancer Association and a grant from the Israel Science Foundation.

Author information

Author notes

  1. Ronit Elhasid and Dvora Sahar: These authors contributed equally to this paper.

Authors and Affiliations

  1. Pediatric-Hemato-Oncology Department. Rambam Medical Center, Bat-Galim, Haifa, 31096, Israel

    Ronit Elhasid & Miriam Ben-Arush

  2. Molecular Hematology Lab, Rambam Medical Center, Bat-Galim, Haifa, 31096, Israel

    Dvora Sahar

  3. Pathology Department, Apoptosis and Carcinogenesis Research Lab, Rambam Medical Center, Bat-Galim, Haifa, 31096, Israel

    Ayellet Merling, Yifat Zivony, Asaf Rotem & Sarit Larisch

  4. Pediatric Hemato Oncology and the Cancer Research Center, Sheba Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel Hashomer, 52621, Israel

    Shai Izraeli

  5. Migal-Galilee Technology Center, Human Molecular Genetics, PO Box 831, Kiryat-Shmona, 11016, Israel

    Dani Bercovich

Authors
  1. Ronit Elhasid
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dvora Sahar
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ayellet Merling
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yifat Zivony
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Asaf Rotem
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Miriam Ben-Arush
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Shai Izraeli
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Dani Bercovich
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Sarit Larisch
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sarit Larisch.

Additional information

Supplementary Information accompanies the paper on Oncogene website (http://www.nature.com/onc)

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Elhasid, R., Sahar, D., Merling, A. et al. Mitochondrial pro-apoptotic ARTS protein is lost in the majority of acute lymphoblastic leukemia patients. Oncogene 23, 5468–5475 (2004). https://doi.org/10.1038/sj.onc.1207725

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1207725

Keywords

This article is cited by

Search

Advanced search

Quick links