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.

  • Review
  • Published:

Bax Inhibitor 1 in apoptosis and disease

Abstract

Bax inhibitor 1 (BI-1) was originally discovered as an inhibitor of Bax-induced apoptosis; this review highlights the fundamental importance of BI-1 in a wider context, including in tissue homeostasis and as a regulator of cellular stress. BI-1 has been shown to interact with a broad range of partners to inhibit many facets of apoptosis, such as reactive oxygen species production, cytosolic acidification and calcium levels as well as endoplasmic reticulum stress signalling pathways. BI-1's anti-apoptotic action initially enables the cell to adapt to stress, although if the stress is prolonged or severe the actions of BI-1 may promote apoptosis. This almost universal anti-apoptotic capacity has been shown to be manipulated during infection with enteropathogenic and enterohaemorrhagic Escherichia coli inhibiting host cell death through direct interaction between their effector NleH and BI-1. In addition, BI-1 activity is important in a large number of cancers, promoting metastasis by modulating actin dynamics, a process dependent upon the BI-1 C-terminus and BI-1:actin interaction. Manipulation of BI-1 therefore has the potential for significant therapeutic benefit in a wide range of human diseases.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  • Ahn T, Yun CH, Chae HZ, Kim HR, Chae HJ . (2009). Ca2+/H+ antiporter-like activity of human recombinant Bax inhibitor-1 reconstituted into liposomes. FEBS J 276: 2285–2291.

    Article  CAS  PubMed  Google Scholar 

  • Ahn T, Yun CH, Kim HR, Chae HJ . (2010). Cardiolipin, phosphatidylserine, and BH4 domain of Bcl-2 family regulate Ca2+/H+ antiporter activity of human Bax inhibitor-1. Cell Calcium 47: 387–396.

    Article  CAS  PubMed  Google Scholar 

  • Bailly-Maitre B, Fondevila C, Kaldas F, Droin N, Luciano F, Ricci JE et al. (2006). Cytoprotective gene bi-1 is required for intrinsic protection from endoplasmic reticulum stress and ischemia-reperfusion injury. Proc Natl Acad Sci USA 103: 2809–2814.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Burns TF, El-Deiry WS . (2001). Identification of inhibitors of TRAIL-induced death (ITIDs) in the TRAIL-sensitive colon carcinoma cell line SW480 using a genetic approach. J Biol Chem 276: 37879–37886.

    CAS  PubMed  Google Scholar 

  • Cande C, Cecconi F, Dessen P, Kroemer G . (2002). Apoptosis-inducing factor (AIF): key to the conserved caspase-independent pathways of cell death? J Cell Sci 115: 4727–4734.

    Article  CAS  PubMed  Google Scholar 

  • Caron E, Crepin VF, Simpson N, Knutton S, Garmendia J, Frankel G . (2006). Subversion of actin dynamics by EPEC and EHEC. Curr Opin Microbiol 9: 40–45.

    Article  CAS  PubMed  Google Scholar 

  • Chae HJ, Kim HR, Xu C, Bailly-Maitre B, Krajewska M, Krajewski S et al. (2004). BI-1 regulates an apoptosis pathway linked to endoplasmic reticulum stress. Mol Cell 15: 355–366.

    Article  CAS  PubMed  Google Scholar 

  • Chipuk JE, Moldoveanu T, Llambi F, Parsons MJ, Green DR . (2010). The BCL-2 family reunion. Mol Cell 37: 299–310.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Circu ML, Aw TY . (2010). Reactive oxygen species, cellular redox systems, and apoptosis. Free Radic Biol Med 48: 749–762.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Crane JK, McNamara BP, Donnenberg MS . (2001). Role of EspF in host cell death induced by enteropathogenic Escherichia coli. Cell Microbiol 3: 197–211.

    Article  CAS  PubMed  Google Scholar 

  • del Carmen Garcia Molina Wolgien M, da Silva ID, Villanova FE, Yumi Otsuka A, Borra RC, Lima Reis LF et al. (2005). Differential gene expression assessed by cDNA microarray analysis in breast cancer tissue under tamoxifen treatment. Eur J Gynaecol Oncol 26: 501–504.

    CAS  PubMed  Google Scholar 

  • Elmore S . (2007). Apoptosis: a review of programmed cell death. Toxicol Pathol 35: 495–516.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ferri KF, Kroemer G . (2001). Mitochondria—the suicide organelles. Bioessays 23: 111–115.

    Article  CAS  PubMed  Google Scholar 

  • Green DR, Reed JC . (1998). Mitochondria and apoptosis. Science 281: 1309–1312.

    Article  CAS  PubMed  Google Scholar 

  • Grzmil M, Kaulfuss S, Thelen P, Hemmerlein B, Schweyer S, Obenauer S et al. (2006). Expression and functional analysis of Bax inhibitor-1 in human breast cancer cells. J Pathol 208: 340–349.

    Article  CAS  PubMed  Google Scholar 

  • Hemrajani C, Berger CN, Robinson KS, Marches O, Mousnier A, Frankel G . (2010). NleH effectors interact with Bax inhibitor-1 to block apoptosis during enteropathogenic Escherichia coli infection. Proc Natl Acad Sci USA 107: 3129–3134.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hengartner MO . (2000). The biochemistry of apoptosis. Nature 407: 770–776.

    Article  CAS  PubMed  Google Scholar 

  • Hetz C, Bernasconi P, Fisher J, Lee AH, Bassik MC, Antonsson B et al. (2006). Proapoptotic BAX and BAK modulate the unfolded protein response by a direct interaction with IRE1alpha. Science 312: 572–576.

    Article  CAS  PubMed  Google Scholar 

  • Igney FH, Krammer PH . (2002). Death and anti-death: tumour resistance to apoptosis. Nat Rev Cancer 2: 277–288.

    Article  CAS  PubMed  Google Scholar 

  • Imaizumi K, Miyoshi K, Katayama T, Yoneda T, Taniguchi M, Kudo T et al. (2001). The unfolded protein response and Alzheimer′s disease. Biochim Biophys Acta 1536: 85–96.

    Article  CAS  PubMed  Google Scholar 

  • Jean JC, Oakes SM, Joyce-Brady M . (1999). The Bax inhibitor-1 gene is differentially regulated in adult testis and developing lung by two alternative TATA-less promoters. Genomics 57: 201–208.

    Article  CAS  PubMed  Google Scholar 

  • Kim HR, Lee GH, Cho EY, Chae SW, Ahn T, Chae HJ . (2009). Bax inhibitor 1 regulates ER-stress-induced ROS accumulation through the regulation of cytochrome P450 2E1. J Cell Sci 122: 1126–1133.

    Article  CAS  PubMed  Google Scholar 

  • Kim HR, Lee GH, Ha KC, Ahn T, Moon JY, Lee BJ et al. (2008). Bax Inhibitor-1 Is a pH-dependent regulator of Ca2+ channel activity in the endoplasmic reticulum. J Biol Chem 283: 15946–15955.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim R, Emi M, Tanabe K, Murakami S . (2006). Role of the unfolded protein response in cell death. Apoptosis 11: 5–13.

    Article  CAS  PubMed  Google Scholar 

  • Kim R, Tanabe K, Uchida Y, Emi M, Inoue H, Toge T . (2002). Current status of the molecular mechanisms of anticancer drug-induced apoptosis. The contribution of molecular-level analysis to cancer chemotherapy. Cancer Chemother Pharmacol 50: 343–352.

    Article  CAS  PubMed  Google Scholar 

  • Kohno K . (2010). Stress-sensing mechanisms in the unfolded protein response: similarities and differences between yeast and mammals. J Biochem 147: 27–33.

    Article  CAS  PubMed  Google Scholar 

  • Krajewski S, Krajewska M, Turner BC, Pratt C, Howard B, Zapata JM et al. (1999). Prognostic significance of apoptosis regulators in breast cancer. Endocr Relat Cancer 6: 29–40.

    Article  CAS  PubMed  Google Scholar 

  • Kuo TH, Kim HR, Zhu L, Yu Y, Lin HM, Tsang W . (1998). Modulation of endoplasmic reticulum calcium pump by Bcl-2. Oncogene 17: 1903–1910.

    Article  CAS  PubMed  Google Scholar 

  • Kurokawa H, Nishio K, Fukumoto H, Tomonari A, Suzuki T, Saijo N . (1999). Alteration of caspase-3 (CPP32/Yama/apopain) in wild-type MCF-7, breast cancer cells. Oncol Rep 6: 33–37.

    CAS  PubMed  Google Scholar 

  • Kvansakul M, Yang H, Fairlie WD, Czabotar PE, Fischer SF, Perugini MA et al. (2008). Vaccinia virus anti-apoptotic F1L is a novel Bcl-2-like domain-swapped dimer that binds a highly selective subset of BH3-containing death ligands. Cell Death Differ 15: 1564–1571.

    Article  CAS  PubMed  Google Scholar 

  • Lebiedzinska M, Szabadkai G, Jones AW, Duszynski J, Wieckowski MR . (2009). Interactions between the endoplasmic reticulum, mitochondria, plasma membrane and other subcellular organelles. Int J Biochem Cell Biol 41: 1805–1816.

    Article  CAS  PubMed  Google Scholar 

  • Lee GH, Ahn T, Kim DS, Park SJ, Lee YC, Yoo WH et al. (2010a). Bax inhibitor 1 increases cell adhesion through actin polymerization: involvement of calcium and actin binding. Mol Cell Biol 30: 1800–1813.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee GH, Kim HK, Chae SW, Kim DS, Ha KC, Cuddy M et al. (2007). Bax inhibitor-1 regulates endoplasmic reticulum stress-associated reactive oxygen species and heme oxygenase-1 expression. J Biol Chem 282: 21618–21628.

    Article  CAS  PubMed  Google Scholar 

  • Lee GH, Yan C, Shin SJ, Hong SC, Ahn T, Moon A et al. (2010b). BAX inhibitor-1 enhances cancer metastasis by altering glucose metabolism and activating the sodium-hydrogen exchanger: the alteration of mitochondrial function. Oncogene 29: 2130–2141.

    Article  CAS  PubMed  Google Scholar 

  • Lima RT, Martins LM, Guimaraes JE, Sambade C, Vasconcelos MH . (2004). Specific downregulation of bcl-2 and xIAP by RNAi enhances the effects of chemotherapeutic agents in MCF-7 human breast cancer cells. Cancer Gene Ther 11: 309–316.

    Article  CAS  PubMed  Google Scholar 

  • Lisbona F, Rojas-Rivera D, Thielen P, Zamorano S, Todd D, Martinon F et al. (2009). BAX inhibitor-1 is a negative regulator of the ER stress sensor IRE1alpha. Mol Cell 33: 679–691.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Madeo F, Herker E, Maldener C, Wissing S, Lachelt S, Herlan M et al. (2002). A caspase-related protease regulates apoptosis in yeast. Mol Cell 9: 911–917.

    Article  CAS  PubMed  Google Scholar 

  • Nieto N, Friedman SL, Cederbaum AI . (2002). Stimulation and proliferation of primary rat hepatic stellate cells by cytochrome P450 2E1-derived reactive oxygen species. Hepatology 35: 62–73.

    Article  CAS  PubMed  Google Scholar 

  • Ogata M, Hino S, Saito A, Morikawa K, Kondo S, Kanemoto S et al. (2006). Autophagy is activated for cell survival after endoplasmic reticulum stress. Mol Cell Biol 26: 9220–9231.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Plopper GE, McNamee HP, Dike LE, Bojanowski K, Ingber DE . (1995). Convergence of integrin and growth factor receptor signaling pathways within the focal adhesion complex. Mol Biol Cell 6: 1349–1365.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ravi R, Bedi A . (2002). Requirement of BAX for TRAIL/Apo2L-induced apoptosis of colorectal cancers: synergism with sulindac-mediated inhibition of Bcl-x(L). Cancer Res 62: 1583–1587.

    CAS  PubMed  Google Scholar 

  • Reshkin SJ, Bellizzi A, Caldeira S, Albarani V, Malanchi I, Poignee M et al. (2000). Na+/H+ exchanger-dependent intracellular alkalinization is an early event in malignant transformation and plays an essential role in the development of subsequent transformation-associated phenotypes. FASEB J 14: 2185–2197.

    Article  CAS  PubMed  Google Scholar 

  • Rizzuto R, Pinton P, Ferrari D, Chami M, Szabadkai G, Magalhaes PJ et al. (2003). Calcium and apoptosis: facts and hypotheses. Oncogene 22: 8619–8627.

    Article  CAS  PubMed  Google Scholar 

  • Rong J, Chen L, Toth JI, Tcherpakov M, Petroski MD, Reed JC . (2011). BAR, an endoplasmic reticulum-associated E3 ubiquitin ligase, modulates BI-1 protein stability and function in ER stress. J Biol Chem 206: 1453–1463.

    Article  Google Scholar 

  • Rong YP, Bultynck G, Aromolaran AS, Zhong F, Parys JB, De Smedt H et al. (2009). The BH4 domain of Bcl-2 inhibits ER calcium release and apoptosis by binding the regulatory and coupling domain of the IP3 receptor. Proc Natl Acad Sci USA 106: 14397–14402.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Scaffidi C, Fulda S, Srinivasan A, Friesen C, Li F, Tomaselli KJ et al. (1998). Two CD95 (APO-1/Fas) signaling pathways. EMBO J 17: 1675–1687.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schmits R, Cochlovius B, Treitz G, Regitz E, Ketter R, Preuss KD et al. (2002). Analysis of the antibody repertoire of astrocytoma patients against antigens expressed by gliomas. Int J Cancer 98: 73–77.

    Article  CAS  PubMed  Google Scholar 

  • Shiraishi H, Okamoto H, Yoshimura A, Yoshida H . (2006). ER stress-induced apoptosis and caspase-12 activation occurs downstream of mitochondrial apoptosis involving Apaf-1. J Cell Sci 119: 3958–3966.

    Article  CAS  PubMed  Google Scholar 

  • Srinivasula SM, Ahmad M, MacFarlane M, Luo Z, Huang Z, Fernandes-Alnemri T et al. (1998). Generation of constitutively active recombinant caspases-3 and -6 by rearrangement of their subunits. J Biol Chem 273: 10107–10111.

    Article  CAS  PubMed  Google Scholar 

  • Tanaka R, Ishiyama T, Uchihara T, Inadome Y, Iijima T, Morishita Y et al. (2006). Expression of the Bax inhibitor-1 gene in pulmonary adenocarcinoma. Cancer 106: 648–653.

    Article  CAS  PubMed  Google Scholar 

  • Tannock IF, Rotin D . (1989). Acid pH in tumors and its potential for therapeutic exploitation. Cancer Res 49: 4373–4384.

    CAS  PubMed  Google Scholar 

  • Urano W, Taniguchi A, Anzai N, Inoue E, Kanai Y, Yamanaka M et al. (2010). Sodium-dependent phosphate cotransporter type 1 sequence polymorphisms in male patients with gout. Ann Rheum Dis 69: 1232–1234.

    Article  CAS  PubMed  Google Scholar 

  • Wahl ML, Pooler PM, Briand P, Leeper DB, Owen CS . (2000). Intracellular pH regulation in a nonmalignant and a derived malignant human breast cell line. J Cell Physiol 183: 373–380.

    Article  CAS  PubMed  Google Scholar 

  • Wang E, Marcotte R, Petroulakis E . (1999). Signaling pathway for apoptosis: a racetrack for life or death. J Cell Biochem 75 (Suppl 32–33): 95–102.

    Article  Google Scholar 

  • Wyllie AH . (2010). ‘Where, O death, is thy sting?’ A brief review of apoptosis biology. Mol Neurobiol 42: 4–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xu C, Bailly-Maitre B, Reed JC . (2005). Endoplasmic reticulum stress: cell life and death decisions. J Clin Invest 115: 2656–2664.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xu Q, Reed JC . (1998). Bax inhibitor-1, a mammalian apoptosis suppressor identified by functional screening in yeast. Mol Cell 1: 337–346.

    Article  CAS  PubMed  Google Scholar 

  • Yang L, Cao Z, Yan H, Wood WC . (2003). Coexistence of high levels of apoptotic signaling and inhibitor of apoptosis proteins in human tumor cells: implication for cancer specific therapy. Cancer Res 63: 6815–6824.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Abigail Clements is supported by a Marie Curie fellowship FP7-PEOPLE-2009-IIF. This work was supported by a grant from the Wellcome Trust.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to G Frankel.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Robinson, K., Clements, A., Williams, A. et al. Bax Inhibitor 1 in apoptosis and disease. Oncogene 30, 2391–2400 (2011). https://doi.org/10.1038/onc.2010.636

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2010.636

Keywords

This article is cited by

Search

Quick links