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Bfl-1/A1 functions, similar to Mcl-1, as a selective tBid and Bak antagonist

Oncogene volume 27, pages 1421–1428 (2008)Cite this article

Abstract

The prosurvival Bcl-2-family member Bfl-1/A1 is a transcriptional target of nuclear factor-κB (NF-κB) that is overexpressed in many human tumors and is a means by which NF-κB inhibits apoptosis, but its mode of action is controversial. To better understand how Bfl-1 functions, we investigated its interaction with proapoptotic multidomain proteins Bax and Bak, and the BH3-only proteins Bid and tBid. We demonstrate that in living cells Bfl-1 selectively interacts with Bak and tBid, but not with Bax or Bid. Bfl-1/Bak interaction is functional as Bfl-1 suppressed staurosporine (STS)-induced apoptosis in wild-type and Bax-deficient cells, but not in Bak−/− cells. We also show that Bfl-1 blocks tumor necrosis factor-α (TNFα)-induced activation of Bax indirectly, via association with tBid. C-terminal deletion decreased Bfl-1's interaction with Bak and tBid and reduced its ability to suppress Bak- and tBid-mediated cell death. These data indicate that Bfl-1 utilizes different mechanisms to suppress apoptosis depending on the stimulus. Bfl-1 associates with tBid to prevent activation of proapoptotic Bax and Bak, and it also interacts directly with Bak to antagonize Bak-mediated cell death, similar to Mcl-1. Thus, part of the protective function of NF-κB is to induce Mcl-1-like activity by upregulating Bfl-1.

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References

  • Breitschopf K, Zeiher AM, Dimmeler S . (2000). Ubiquitin-mediated degradation of the proapoptotic active form of bid. A functional consequence on apoptosis induction. J Biol Chem 275: 21648–21652.

    Article  CAS  Google Scholar 

  • Certo M, Del Gaizo Moore V, Nishino M, Wei G, Korsmeyer S, Armstrong SA et al. (2006). Mitochondria primed by death signals determine cellular addiction to anti-apoptotic BCL-2 family members. Cancer Cell 9: 351–365.

    Article  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 

  • Cheng EH, Wei M, Weiler S, Flavell RA, Mak TW, Lindsten T et al. (2001). BCL-2, BCL-XL sequester BH3 domain-only molecules preventing BAX- and BAK-mediated mitochondrial apoptosis. Mol Cell 8: 705–711.

    Article  CAS  Google Scholar 

  • Clohessy JG, Zhuang J, de Boer J, Gil-Gomez G, Brady HJ . (2006). Mcl-1 interacts with truncated Bid and inhibits its induction of cytochrome c release and its role in receptor-mediated apoptosis. J Biol Chem 281: 5750–5759.

    Article  CAS  Google Scholar 

  • Cory S, Huang DC, Adams JM . (2003). The Bcl-2 family: roles in cell survival and oncogenesis. Oncogene 22: 8590–8607.

    Article  CAS  Google Scholar 

  • Cuconati A, Degenhardt K, Sundararajan R, Anschel A, White E . (2002). Bak and Bax function to limit adenovirus replication through apoptosis induction. J Virol 76: 4547–4558.

    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 

  • Cuconati A, White E . (2002). Viral homologues of Bcl-2: role of apoptosis in the regulation of virus infection. Genes Dev 16: 2465–2478.

    Article  CAS  Google Scholar 

  • D’Sa-Eipper C, Chinnadurai G . (1998). Functional dissection of Bfl-1, a Bcl-2 homolog: anti-apoptosis, oncogene-cooperation and cell proliferation activities. Oncogene 16: 3105–3114.

    Article  Google Scholar 

  • Degenhardt K, Sundararajan R, Lindsten T, Thompson C, White E . (2002). Bax and Bak independently promote cytochrome C release from mitochondria. J Biol Chem 277: 14127–14134.

    Article  CAS  Google Scholar 

  • Desagher S, Osen-Sand A, Nichols A, Eskes R, Montessuit S, Lauper S et al. (1999). Bid-induced conformational change of Bax is responsible for mitochondrial cytochrome c release during apoptosis. J Cell Biol 144: 891–901.

    Article  CAS  Google Scholar 

  • Epand RF, Martinou JC, Fornallaz-Mulhauser M, Hughes DW, Epand RM . (2002). The apoptotic protein tBid promotes leakage by altering membrane curvature. J Biol Chem 277: 32632–32639.

    Article  CAS  Google Scholar 

  • Gélinas C, White E . (2005). BH3-only proteins in control: specificity regulates MCL-1 and BAK-mediated apoptosis. Genes Dev 19: 1263–1268.

    Article  Google Scholar 

  • Grinberg M, Sarig R, Zaltsman Y, Frumkin D, Grammatikakis N, Reuveny E et al. (2002). tBID homooligomerizes in the mitochondrial membrane to induce apoptosis. J Biol Chem 277: 12237–12245.

    Article  CAS  Google Scholar 

  • Grumont RJ, Rourke IJ, Gerondakis S . (1999). Rel-dependent induction of A1 transcription is required to protect B cells from antigen receptor ligation-induced apoptosis. Genes Dev 13: 400–411.

    Article  CAS  Google Scholar 

  • Herold MJ, Zeitz J, Pelzer C, Kraus C, Peters A, Wohlleben G et al. (2006). The stability and anti-apoptotic function of A1 are controlled by its C terminus. J Biol Chem 281: 13663–13671.

    Article  CAS  Google Scholar 

  • Holmgreen SP, Huang DC, Adams JM, Cory S . (1999). Survival activity of Bcl-2 homologs Bcl-w and A1 only partially correlates with their ability to bind proapoptotic family members. Cell Death Differ 6: 525–532.

    Article  CAS  Google Scholar 

  • Hsu YT, Youle RJ . (1998). Bax in murine thymus is a soluble monomeric protein that displays differential detergent-induced conformations. J Biol Chem 273: 10777–10783.

    Article  CAS  Google Scholar 

  • Karsan A, Yee E, Harlan JM . (1996). Endothelial cell death induced by tumor necrosis factor-alpha is inhibited by the Bcl-2 family member, A1. J Biol Chem 271: 27201–27204.

    Article  CAS  Google Scholar 

  • Konopleva M, Contractor R, Tsao T, Samudio I, Ruvolo PP, Kitada S et al. (2006). Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia. Cancer Cell 10: 375–388.

    Article  CAS  Google Scholar 

  • Kucharczak JF, Simmons MJ, Duckett CS, Gelinas C . (2005). Constitutive proteasome-mediated turnover of Bfl-1/A1 and its processing in response to TNF receptor activation in FL5.2 pro-B cells convert it into a prodeath factor. Cell Death Differ 12: 1225–1239.

    Article  CAS  Google Scholar 

  • Kuwana T, Bouchier-Hayes L, Chipuk JE, Bonzon C, Sullivan BA, Green DR et al. (2005). BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer therapeutics. Mol Cell 17: 525–535.

    Article  CAS  Google Scholar 

  • Lee HH, Dadgostar H, Cheng Q, Shu J, Cheng G . (1999). NF-kappaB-mediated upregulation of Bcl-x and Bfl-1/A1 is required for CD40 survival signaling in B lymphocytes. Proc Natl Acad Sci USA 96: 9136–9141.

    Article  CAS  Google Scholar 

  • Letai A . (2006). Restoring cancer's death sentence. Cancer Cell 10: 343–345.

    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 

  • Michels J, Johnson PW, Packham G . (2005). Mcl-1. Int J Biochem Cell Biol 37: 267–271.

    Article  CAS  Google Scholar 

  • Nguyen M, Millar DG, Yong VW, Korsmeyer SJ, Shore GC . (1993). Targeting of Bcl-2 to the mitochondrial outer membrane by a COOH-terminal signal anchor sequence. J Biol Chem 268: 25265–25268.

    CAS  Google Scholar 

  • Oltvai ZN, Milliman CL, Korsmeyer SJ . (1993). Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell 74: 609–619.

    Article  CAS  Google Scholar 

  • Perez D, White E . (2000). TNF-alpha signals apoptosis through a bid-dependent conformational change in Bax that is inhibited by E1B 19K. Mol Cell 6: 53–63.

    Article  CAS  Google Scholar 

  • Sedlak TW, Oltvai ZN, Yang E, Wang K, Boise LH, Thompson CB et al. (1995). Multiple Bcl-2 family members demonstrate selective dimerization with Bax. Proc Natl Acad Sci USA 92: 7834–7838.

    Article  CAS  Google Scholar 

  • Somogyi RD, Wu Y, Orlofsky A, Prystowsky MB . (2001). Transient expression of the Bcl-2 family member, A1-a, results in nuclear localization and resistance to staurosporine-induced apoptosis. Cell Death Differ 8: 785–793.

    Article  CAS  Google Scholar 

  • van Delft MF, Wei AH, Mason KD, Vandenberg CJ, Chen L, Czabotar PE et al. (2006). The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized. Cancer Cell 10: 389–399.

    Article  CAS  Google Scholar 

  • Wang CY, Guttridge DC, Mayo MW, Baldwin Jr AS . (1999). NF-kappaB induces expression of the Bcl-2 homologue A1/Bfl-1 to preferentially suppress chemotherapy-induced apoptosis. Mol Cell Biol 19: 5923–5929.

    Article  CAS  Google Scholar 

  • Wei MC, Lindsten T, Mootha VK, Weiler S, Gross A, Ashiya M et al. (2000). tBID, a membrane-targeted death ligand, oligomerizes BAK to release cytochrome c. Genes Dev 14: 2060–2071.

    CAS  Google Scholar 

  • Wei MC, Zong WX, Cheng EH, Lindsten T, Panoutsakopoulou V, Ross AJ et al. (2001). Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death. Science 292: 727–730.

    Article  CAS  Google Scholar 

  • Werner AB, de Vries E, Tait SWG, Bontjer I, Borst J . (2002). Bcl-2 family member Bfl-1/A1 sequesters truncated Bid to inhibit its collaboration with proapoptotic Bak or Bax. J Biol Chem 277: 22781–22788.

    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 

  • Yi X, Yin XM, Dong Z . (2003). Inhibition of Bid-induced apoptosis by Bcl-2. tBid insertion, Bax translocation, and Bax/Bak oligomerization suppressed. J Biol Chem 278: 16992–16999.

    Article  CAS  Google Scholar 

  • Zhang H, Cowan-Jacob SW, Simonen M, Greenhalf W, Heim J, Meyhack B . (2000). Structural basis of Bfl-1 for its interaction with Bax and anti-apoptotic action in mammalian and yeast cells. J Biol Chem 275: 11092–11099.

    Article  CAS  Google Scholar 

  • Zong WX, Edelstein LC, Chen C, Bash J, Gélinas C . (1999). The prosurvival Bcl-2 homolog Bfl-1/A1 is a direct transcriptional target of NF-κB that blocks TNFα-induced apoptosis. Genes Dev 13: 382–387.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank R Sundararajan, D Perez and N Gupta for discussions. This work was supported by NIH Grant CA083937, the Charlotte Geyer Foundation and the Foundation of UMDNJ. MJS was partially supported by NIH predoctoral training Grant GM08360.

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Author notes

  1. M J Simmons

    Present address: 6Present address: Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01650, USA.,

  2. W-X Zong

    Present address: 7Present address: Department of Molecular Genetics and Microbiology, SUNY-Stony Brook, Stony Brook, NY 11794-5222, USA.,

Authors and Affiliations

  1. Center for Advanced Biotechnology and Medicine, UMDNJ—Robert Wood Johnson Medical School, Piscataway, NJ, USA

    M J Simmons, G Fan, W-X Zong, K Degenhardt, E White & C Gélinas

  2. Graduate Program in Biochemistry and Molecular Biology, UMDNJ—Robert Wood Johnson Medical School, Piscataway, NJ, USA

    M J Simmons, G Fan & W-X Zong

  3. Department of Molecular Biology and Biochemistry, Rutgers University, New Brunswick, NJ, USA

    E White

  4. Cancer Institute of New Jersey, New Brunswick, NJ, USA

    E White & C Gélinas

  5. Department of Biochemistry, UMDNJ—Robert Wood Johnson Medical School, Piscataway, NJ, USA

    C Gélinas

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Correspondence to C Gélinas.

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

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Simmons, M., Fan, G., Zong, WX. et al. Bfl-1/A1 functions, similar to Mcl-1, as a selective tBid and Bak antagonist. Oncogene 27, 1421–1428 (2008). https://doi.org/10.1038/sj.onc.1210771

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