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 Article
  • Published:

TGFβ-mediated apoptosis of Burkitt's lymphoma BL41 cells is associated with the relocation of mitochondrial BimEL

Oncogene volume 27, pages 3446–3456 (2008)Cite this article

Abstract

In this study, we showed that the transforming growth factor β (TGFβ)-mediated apoptosis of Burkitt's lymphoma BL41 cells is dependent on the BH3-only protein Bim. In contrast to what has been observed with other cell types, TGFβ activation did not promote Bim upregulation in BL41 cells, but instead resulted in Bim release from the mitochondria. Indeed, Bim levels were high in healthy BL41 cells, in which they dimerized with the Bcl-2-like protein Mcl-1 at the mitochondrial surface. In healthy and TGFβ-activated BL41 cells, unlike in epithelial cells or hepatocytes, Bim did not associate with Bcl-2 or Bcl-xL. TGFβ activation of BL41 cells triggered the p38-dependent activation of caspase-8, causing the cleavage of Mcl-1 and the transfer of Bim from the mitochondria to the cytoskeleton. In addition to mitochondrial activation, this relocation of Bim may facilitate the complete demise of a cell death that is beyond the commitment point to apoptosis and may represent a hallmark of the TGFβ-mediated apoptosis of human lymphoma B cells.

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

  • Alvarado-Kristensson M, Melander F, Leandersson K, Ronnstrand L, Wernstedt C, Andersson T . (2004). p38-MAPK signals survival by phosphorylation of caspase-8 and caspase-3 in human neutrophils. J Exp Med 199: 449–458.

    Article  CAS  Google Scholar 

  • Bingle CD, Craig RW, Swales BM, Singleton V, Zhou P, Whyte MK . (2000). Exon skipping in Mcl-1 results in a Bcl-2 homology domain 3 only gene product that promotes cell death. J Biol Chem 275: 22136–22146.

    Article  CAS  Google Scholar 

  • Bouillet P, Cory S, Zhang LC, Strasser A, Adams JM . (2001). Degenerative disorders caused by Bcl-2 deficiency prevented by loss of its BH3-only antagonist Bim. Dev Cell 1: 645–653.

    Article  CAS  Google Scholar 

  • Bouillet P, Metcalf D, Huang DC, Tarlinton DM, Kay TW, Kontgen F et al. (1999). Proapoptotic Bcl-2 relative Bim required for certain apoptotic responses, leukocyte homeostasis, and to preclude autoimmunity. Science 286: 1735–1738.

    Article  CAS  Google Scholar 

  • Cai B, Chang SH, Becker EB, Bonni A, Xia Z . (2006). p38 MAP kinase mediates apoptosis through phosphorylation of BimEL at Ser-65. J Biol Chem 281: 25215–25222.

    Article  CAS  Google Scholar 

  • Chaouchi N, Arvanitakis L, Auffredou MT, Blanchard DA, Vazquez A, Sharma S . (1995). Characterization of transforming growth factor-beta 1 induced apoptosis in normal human B cells and lymphoma B cell lines. Oncogene 11: 1615–1622.

    CAS  Google Scholar 

  • Chen L, Willis SN, Wei A, Smith BJ, Fletcher JI, Hinds MG et al. (2005). Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function. Mol Cell 17: 393–403.

    Article  CAS  Google Scholar 

  • Choi WS, Eom DS, Han BS, Kim WK, Han BH, Choi EJ et al. (2004). Phosphorylation of p38 MAPK induced by oxidative stress is linked to activation of both caspase-8- and -9-mediated apoptotic pathways in dopaminergic neurons. J Biol Chem 279: 20451–20460.

    Article  CAS  Google Scholar 

  • Clybouw C, McHichi B, Mouhamad S, Auffredou MT, Bourgeade MF, Sharma S et al. (2005). EBV infection of human B lymphocytes leads to down-regulation of Bim expression: relationship to resistance to apoptosis. J Immunol 175: 2968–2973.

    Article  CAS  Google Scholar 

  • Cory S, Huang DC, Adams JM . (2003). The Bcl-2 family: roles in cell survival and oncogenesis. Oncogene 22: 8590–85607.

    Article  CAS  Google Scholar 

  • Cuconati A, Mukherjee C, Perez D, White E . (2003). DNA damage response and MCL-1 destruction initiate apoptosis in adenovirus-infected cells. Genes Dev 17: 2922–2932.

    Article  CAS  Google Scholar 

  • Danial NN, Korsmeyer SJ . (2004). Cell death: critical control points. Cell 116: 205–219.

    Article  CAS  Google Scholar 

  • Dijkers PF, Medema RH, Lammers JW, Koenderman L, Coffer PJ . (2000). Expression of the pro-apoptotic Bcl-2 family member Bim is regulated by the forkhead transcription factor FKHR-L1. Curr Biol 10: 1201–1204.

    Article  CAS  Google Scholar 

  • Domina AM, Vrana JA, Gregory MA, Hann SR, Craig RW . (2004). MCL1 is phosphorylated in the PEST region and stabilized upon ERK activation in viable cells, and at additional sites with cytotoxic okadaic acid or taxol. Oncogene 23: 5301–5315.

    Article  CAS  Google Scholar 

  • El McHichi B, Hadji A, Vazquez A, Leca G . (2007). p38 MAPK and MSK1 mediate caspase-8 activation in manganese-induced mitochondria-dependent cell death. Cell Death Differ 14: 1826–1936.

    Article  CAS  Google Scholar 

  • Ewings KE, Hadfield-Moorhouse K, Wiggins CM, Wickenden JA, Balmanno K, Gilley R et al. (2007). ERK1/2-dependent phosphorylation of Bim(EL) promotes its rapid dissociation from Mcl-1 and Bcl-x(L). EMBO J 26: 2856–2867.

    Article  CAS  Google Scholar 

  • Gomez-Bougie P, Bataille R, Amiot M . (2004). The imbalance between Bim and Mcl-1 expression controls the survival of human myeloma cells. Eur J Immunol 34: 3156–3164.

    Article  CAS  Google Scholar 

  • Gomez-Bougie P, Bataille R, Amiot M . (2005). Endogenous association of Bim BH3-only protein with Mcl-1, Bcl-xL and Bcl-2 on mitochondria in human B cells. Eur J Immunol 35: 971–976.

    Article  CAS  Google Scholar 

  • Han J, Goldstein LA, Gastman BR, Froelich CJ, Yin XM, Rabinowich H . (2004). Degradation of Mcl-1 by granzyme B: implications for Bim-mediated mitochondrial apoptotic events. J Biol Chem 279: 22020–22029.

    Article  CAS  Google Scholar 

  • Han J, Goldstein LA, Gastman BR, Rabinowich H . (2006). Interrelated roles for Mcl-1 and BIM in regulation of TRAIL-mediated mitochondrial apoptosis. J Biol Chem 281: 10153–10163.

    Article  CAS  Google Scholar 

  • Herrant M, Jacquel A, Marchetti S, Belhacene N, Colosetti P, Luciano F et al. (2004). Cleavage of Mcl-1 by caspases impaired its ability to counteract Bim-induced apoptosis. Oncogene 23: 7863–7873.

    Article  CAS  Google Scholar 

  • Herrant M, Luciano F, Loubat A, Auberger P . (2002). The protective effect of phorbol esters on Fas-mediated apoptosis in T cells. Transcriptional and posttranscriptional regulation. Oncogene 21: 4957–4968.

    Article  CAS  Google Scholar 

  • Hildeman DA, Zhu Y, Mitchell TC, Bouillet P, Strasser A, Kappler J et al. (2002). Activated T cell death in vivo mediated by proapoptotic Bcl-2 family member bim. Immunity 16: 759–767.

    Article  CAS  Google Scholar 

  • Huang DC, Strasser A . (2000). BH3-Only proteins-essential initiators of apoptotic cell death. Cell 103: 839–842.

    Article  CAS  Google Scholar 

  • Kim H, Rafiuddin-Shah M, Tu HC, Jeffers JR, Zambetti GP, Hsieh JJ et al. (2006). Hierarchical regulation of mitochondrion-dependent apoptosis by BCL-2 subfamilies. Nat Cell Biol 8: 1348–1358.

    Article  CAS  Google Scholar 

  • Kobayashi S, Lee SH, Meng XW, Mott JL, Bronk SF, Werneburg NW et al. (2007). Serine 64 phosphorylation enhances the antiapoptotic function of mcl-1. J Biol Chem 282: 18407–18417.

    Article  CAS  Google Scholar 

  • Kuwana T, Bouchier-Hayes L, Chipuk JE, Bonzon C, Sullivan BA, Green DR et al. (2005). BH3 domains of BH3-only proteins differentially regulate Bax-mediated mitochondrial membrane permeabilization both directly and indirectly. Mol Cell 17: 525–535.

    Article  CAS  Google Scholar 

  • Lei K, Davis RJ . (2003). JNK phosphorylation of Bim-related members of the Bcl2 family induces Bax-dependent apoptosis. Proc Natl Acad Sci USA 100: 2432–2437.

    Article  CAS  Google Scholar 

  • Letai A, Bassik MC, Walensky LD, Sorcinelli MD, Weiler S, Korsmeyer SJ . (2002). Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer therapeutics. Cancer Cell 2: 183–192.

    Article  CAS  Google Scholar 

  • Ley R, Ewings KE, Hadfield K, Howes E, Balmanno K, Cook SJ . (2004). Extracellular signal-regulated kinases 1/2 are serum-stimulated ‘Bim(EL) kinases’ that bind to the BH3-only protein Bim(EL) causing its phosphorylation and turnover. J Biol Chem 279: 8837–8847.

    Article  CAS  Google Scholar 

  • Luciano F, Jacquel A, Colosetti P, Herrant M, Cagnol S, Pages G et al. (2003). Phosphorylation of Bim-EL by Erk1/2 on serine 69 promotes its degradation via the proteasome pathway and regulates its proapoptotic function. Oncogene 22: 6785–6793.

    Article  CAS  Google Scholar 

  • Marani M, Tenev T, Hancock D, Downward J, Lemoine NR . (2002). Identification of novel isoforms of the BH3 domain protein Bim which directly activate Bax to trigger apoptosis. Mol Cell Biol 22: 3577–3589.

    Article  CAS  Google Scholar 

  • Maurer U, Charvet C, Wagman AS, Dejardin E, Green DR . (2006). Glycogen synthase kinase-3 regulates mitochondrial outer membrane permeabilization and apoptosis by destabilization of MCL-1. Mol Cell 21: 749–760.

    Article  CAS  Google Scholar 

  • Michels J, O'Neill JW, Dallman CL, Mouzakiti A, Habens F, Brimmell M et al. (2004). Mcl-1 is required for Akata6 B-lymphoma cell survival and is converted to a cell death molecule by efficient caspase-mediated cleavage. Oncogene 23: 4818–4827.

    Article  CAS  Google Scholar 

  • Mouhamad S, Besnault L, Auffredou MT, Leprince C, Bourgeade MF, Leca G et al. (2004). B cell receptor-mediated apoptosis of human lymphocytes is associated with a new regulatory pathway of Bim isoform expression. J Immunol 172: 2084–2091.

    Article  CAS  Google Scholar 

  • Nijhawan D, Fang M, Traer E, Zhong Q, Gao W, Du F et al. (2003). Elimination of Mcl-1 is required for the initiation of apoptosis following ultraviolet irradiation. Genes Dev 17: 1475–1486.

    Article  CAS  Google Scholar 

  • O'Connor L, Strasser A, O'Reilly LA, Hausmann G, Adams JM, Cory S et al. (1998). Bim: a novel member of the Bcl-2 family that promotes apoptosis. EMBO J 17: 384–395.

    Article  CAS  Google Scholar 

  • Ohgushi M, Kuroki S, Fukamachi H, O'Reilly LA, Kuida K, Strasser A et al. (2005). Transforming growth factor beta-dependent sequential activation of Smad, Bim, and caspase-9 mediates physiological apoptosis in gastric epithelial cells. Mol Cell Biol 25: 10017–10028.

    Article  CAS  Google Scholar 

  • Opferman JT, Letai A, Beard C, Sorcinelli MD, Ong CC, Korsmeyer SJ . (2003). Development and maintenance of B and T lymphocytes requires antiapoptotic MCL-1. Nature 426: 671–676.

    Article  CAS  Google Scholar 

  • Park HJ, Kim BC, Kim SJ, Choi KS . (2002). Role of MAP kinases and their cross-talk in TGF-beta1-induced apoptosis in FaO rat hepatoma cell line. Hepatology 35: 1360–1371.

    Article  CAS  Google Scholar 

  • Park MT, Choi JA, Kim MJ, Um HD, Bae S, Kang CM et al. (2003). Suppression of extracellular signal-related kinase and activation of p38 MAPK are two critical events leading to caspase-8- and mitochondria-mediated cell death in phytosphingosine-treated human cancer cells. J Biol Chem 278: 50624–50634.

    Article  CAS  Google Scholar 

  • Putcha GV, Moulder KL, Golden JP, Bouillet P, Adams JA, Strasser A et al. (2001). Neuron 29: 615–628.

    Article  CAS  Google Scholar 

  • Puthalakath H, Huang DC, O'Reilly LA, King SM, Strasser A . (1999). Induction of BIM, a proapoptotic BH3-only BCL-2 family member, is critical for neuronal apoptosis. Mol Cell 3: 287–396.

    Article  CAS  Google Scholar 

  • Puthalakath H, Strasser A . (2002). Keeping killers on a tight leash: transcriptional and post-translational control of the pro-apoptotic activity of BH3-only proteins. Cell Death Differ 9: 505–512.

    Article  CAS  Google Scholar 

  • Ramjaun AR, Tomlinson S, Eddaoudi A, Downward J . (2007). Upregulation of two BH3-only proteins, Bmf and Bim, during TGF beta-induced apoptosis. Oncogene 26: 970–981.

    Article  CAS  Google Scholar 

  • Schrantz N, Bourgeade MF, Mouhamad S, Leca G, Sharma S, Vazquez A . (2001). p38-mediated regulation of an Fas-associated death domain protein-independent pathway leading to caspase-8 activation during TGFbeta-induced apoptosis in human Burkitt lymphoma B cells BL41. Mol Biol Cell 12: 3139–3151.

    Article  CAS  Google Scholar 

  • Strasser A . (2005). The role of BH3-only proteins in the immune system. Nat Rev Immunol 5: 189–200.

    Article  CAS  Google Scholar 

  • U M, Miyashita T, Shikama Y, Tadokoro K, Yamada M . (2001). Molecular cloning and characterization of six novel isoforms of human Bim, a member of the proapoptotic Bcl-2 family. FEBS Lett 509: 135–141.

    Article  CAS  Google Scholar 

  • Wildey GM, Patil S, Howe PH . (2003). Smad3 potentiates transforming growth factor beta (TGFbeta )-induced apoptosis and expression of the BH3-only protein Bim in WEHI 231 B lymphocytes. J Biol Chem 278: 18069–18077.

    Article  CAS  Google Scholar 

  • Willis SN, Chen L, Dewson G, Wei A, Naik E, Fletcher JI et al. (2005). Proapoptotic Bak is sequestered by Mcl-1 and Bcl-xL, but not Bcl-2, until displaced by BH3-only proteins. Genes Dev 19: 1294–1305.

    Article  CAS  Google Scholar 

  • Willis SN, Fletcher JI, Kaufmann T, van Delft MF, Chen L, Czabotar PE et al. (2007). Apoptosis initiated when BH3 ligands engage multiple Bcl-2 homologs, not Bax or Bak. Science 315: 856–859.

    Article  CAS  Google Scholar 

  • Yoo J, Ghiassi M, Jirmanova L, Balliet AG, Hoffman B, Fornace AJ et al. (2003). Transforming growth factor-beta-induced apoptosis is mediated by Smad-dependent expression of GADD45b through p38 activation. J Biol Chem 278: 43001–43007.

    Article  CAS  Google Scholar 

  • Yu L, Hebert MC, Zhang YE . (2002). TGF-beta receptor-activated p38 MAP kinase mediates Smad-independent TGF-beta responses. EMBO J 21: 3749–3759.

    Article  CAS  Google Scholar 

  • Zhong Q, Gao W, Du F, Wang X . (2005). Mule/ARF-BP1, a BH3-only E3 ubiquitin ligase, catalyzes the polyubiquitination of Mcl-1 and regulates apoptosis. Cell 121: 1085–1095.

    Article  CAS  Google Scholar 

  • Zhu Y, Swanson BJ, Wang M, Hildeman DA, Schaefer BC, Liu X et al. (2004). Constitutive association of the proapoptotic protein Bim with Bcl-2-related proteins on mitochondria in T cells. Proc Natl Acad Sci USA 101: 7681–7686.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by INSERM and grants from the Fondation de France, Association pour la Recherche sur le Cancer (ARC) and Agence Nationale de la Recherche (ANR). CC and BEM hold fellowships from Ministére de la Recherche, Fédération de la Recherche Médicale (FRM) and Société Française d'Hématologie, respectively. We thank Dr P Bouillet (The Walter and Eliza Hall Institute, Australia) for providing us with scrambled and Bim-shRNA.

Author information

Author notes

  1. C Clybouw and B E L Mchichi: These authors contributed equally to this work.

Authors and Affiliations

  1. INSERM U542, Université Paris-Sud, Hôpital Paul Brousse, Villejuif, France

    C Clybouw, B E L Mchichi, A Hadji, A Portier, M T Auffredou, D Arnoult, G Leca & A Vazquez

Authors
  1. C Clybouw
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. B E L Mchichi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A Hadji
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A Portier
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M T Auffredou
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. D Arnoult
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. G Leca
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. A Vazquez
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A Vazquez.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Clybouw, C., E L Mchichi, B., Hadji, A. et al. TGFβ-mediated apoptosis of Burkitt's lymphoma BL41 cells is associated with the relocation of mitochondrial BimEL. Oncogene 27, 3446–3456 (2008). https://doi.org/10.1038/sj.onc.1211009

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1211009

Keywords

This article is cited by

Search

Advanced search

Quick links