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Gene Review

BAX  -  BCL2-associated X protein

Homo sapiens

Synonyms: Apoptosis regulator BAX, BCL2L4, Bcl-2-like protein 4, Bcl2-L-4
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Disease relevance of BAX

  • Loss of BAX also renders colorectal cancer cells resistant to TRAIL/Apo2L-mediated radiosensitization [1].
  • These same v-BCL-2 proteins cooperate with loss of retinoblastoma protein and p53 tumor suppressor function, by inactivating the BAX and BAK apoptotic pathway to promote epithelial solid tumor growth and resistance to chemotherapy [2].
  • This is in clear contrast to other carcinomas where BAX is frequently inactivated which correlates to a poor prognosis (Sturm et al. J. Clin. Oncol. 1999;17:1364-74.). There were no significant differences of the BAX levels between goitres or the adenomas [3].
  • Surprisingly, we observed elevated BAX levels in patients with thyroid carcinomas compared with patients with adenomas (unpaired t-test: p<0.05) or with goitres (p<0.02) [3].
  • We conclude that BAX expression may represent a prognostic indicator for patients with ovarian cancer and that the combined evaluation of BAX and BCL-2 may provide additional prognostic significance [4].

High impact information on BAX

  • Moreover, BCL-XL, BCL-2, and BAX can form ion-conductive pores in artificial membranes [5].
  • The percentage of myocytes labeled with BCL2 (which protects cells against apoptosis) was 1.8 times as high in the hearts of patients with cardiac failure as in the normal hearts, whereas labeling with BAX (which promotes apoptosis) remained constant [6].
  • Bax (Bcl2-associated X protein) is an apoptosis-inducing protein that participates in cell death during normal development and in various diseases [7].
  • To assess the role of BAX in drug-induced apoptosis in human colorectal cancer cells, we generated cells that lack functional BAX genes [8].
  • In contrast, the absence of BAX completely abolished the apoptotic response to the chemopreventive agent sulindac and other nonsteroidal anti-inflammatory drugs (NSAIDs) [8].

Chemical compound and disease context of BAX


Biological context of BAX


Anatomical context of BAX

  • Lastly, immunohistochemical localization of the BAX death-susceptibility protein in the human ovary revealed abundant expression in granulosa cells of early atretic follicles, whereas BAX protein was extremely low or non-detectable in healthy or grossly-atretic follicles [17].
  • These results suggest that the induction of BAX in DAD may enhance the susceptibility of alveolar epithelial cells to apoptosis, whereas BCL-2 expression may contribute to the absence of apoptosis in interstitial myofibroblasts [18].
  • Interestingly, LDFRT treatment in both cell lines with or without Paclitaxel down-regulated nuclear factor kappa B activity and BCL-2 protein expression and simultaneously up-regulated BAX protein [19].
  • Recent genetic studies with fibroblasts derived from mutant mouse embryos indicate that a class of the BCL-2 family proapoptotic proteins (designated BH-123 or multidomain proteins) such as BAX and BAK constitutes an essential component of the core apoptosis machinery in animal cells [20].
  • No germ line BAX mutations were found [21].

Associations of BAX with chemical compounds

  • Coexpression of BAD and NOXA killed wild-type but not Bax, Bak doubly deficient cells or Puma deficient cells with Bim knockdown, indicating that activator BH3-only molecules function downstream of inactivator BH3-only molecules to activate BAX-BAK [13].
  • These results suggest that glutathione-dependent BAX activation in cells with normal CFTR represents an early step in oxidative stress-induced apoptosis of these cells [22].
  • The expression of BCL-2 and BAX, which would occur downstream from p53, was not changed by irradiation and Trolox treatment [23].
  • The cytotoxicity of paclitaxel, vincristine, and doxorubicin was significantly enhanced in BAX transfectants compared with control clones, whereas the cytotoxicity profile of carboplatin, etoposide, and hydroxyurea was unchanged [24].
  • The inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone (zVAD-fmk) successfully blocked this protease activity and prevented FAS-induced death but not BAX-induced death [25].

Physical interactions of BAX

  • The proapoptotic effect of BAX is negatively regulated by its binding with BCL-2 [18].
  • Immunoprecipitation studies and gel shift analysis indicate that c-myb does not directly interact with the BAX promoter or the p53 protein but, rather, cooperates through an indirect mechanism [26].
  • In addition, we screened for mutations in the exons 5-8 of the p53 gene by SSCP-PCR to assess whether mutations in the DNA-binding domain of this upstream regulator of BAX gene transcription are responsible for differences in BAX protein expression [27].
  • BAX-dependent transport of cytochrome c reconstituted in pure liposomes [28].

Regulatory relationships of BAX


Other interactions of BAX

  • Conversely, BAX and BCL2, two other genes associated with regulation of apoptosis, showed no overall correlation with drug sensitivities [32].
  • The strongest correlation among these target genes was between levels of CIP1/WAF1 and BAX [32].
  • Structural basis of BFL-1 for its interaction with BAX and its anti-apoptotic action in mammalian and yeast cells [33].
  • In contrast to promoter activation, we find that the 223 amino acids of the LANA C terminus are sufficient to inhibit p53-mediated activation of the human BAX promoter, indicating that the CBM is not required for all transcription-related functions [34].
  • The MSI pathway frequently has altered transforming growth factor beta receptor II and BAX genes, often beta-catenin, and occasionally p16INK4A and PTEN [35].

Analytical, diagnostic and therapeutic context of BAX


  1. Requirement of BAX for TRAIL/Apo2L-induced apoptosis of colorectal cancers: synergism with sulindac-mediated inhibition of Bcl-x(L). Ravi, R., Bedi, A. Cancer Res. (2002) [Pubmed]
  2. Mechanisms of apoptosis regulation by viral oncogenes in infection and tumorigenesis. White, E. Cell Death Differ. (2006) [Pubmed]
  3. Bax expression in benign and malignant thyroid tumours: dysregulation of wild-type P53 is associated with a high Bax and P21 expression in thyroid carcinoma. Hermann, S., Sturm, I., Mrozek, A., Klosterhalfen, B., Hauptmann, S., Dörken, B., Daniel, P.T. Int. J. Cancer (2001) [Pubmed]
  4. Reduced expression of BAX is associated with poor prognosis in patients with epithelial ovarian cancer: a multifactorial analysis of TP53, p21, BAX and BCL-2. Schuyer, M., van der Burg, M.E., Henzen-Logmans, S.C., Fieret, J.H., Klijn, J.G., Look, M.P., Foekens, J.A., Stoter, G., Berns, E.M. Br. J. Cancer (2001) [Pubmed]
  5. BCL-2 family: regulators of cell death. Chao, D.T., Korsmeyer, S.J. Annu. Rev. Immunol. (1998) [Pubmed]
  6. Apoptosis in the failing human heart. Olivetti, G., Abbi, R., Quaini, F., Kajstura, J., Cheng, W., Nitahara, J.A., Quaini, E., Di Loreto, C., Beltrami, C.A., Krajewski, S., Reed, J.C., Anversa, P. N. Engl. J. Med. (1997) [Pubmed]
  7. Humanin peptide suppresses apoptosis by interfering with Bax activation. Guo, B., Zhai, D., Cabezas, E., Welsh, K., Nouraini, S., Satterthwait, A.C., Reed, J.C. Nature (2003) [Pubmed]
  8. Role of BAX in the apoptotic response to anticancer agents. Zhang, L., Yu, J., Park, B.H., Kinzler, K.W., Vogelstein, B. Science (2000) [Pubmed]
  9. G125A single-nucleotide polymorphism in the human BAX promoter affects gene expression. Moshynska, O., Moshynskyy, I., Misra, V., Saxena, A. Oncogene (2005) [Pubmed]
  10. Evaluation of clinical significance of TP53, BCL-2, BAX and MEK1 expression in 229 ovarian carcinomas treated with platinum-based regimen. Kupryjańczyk, J., Szymańska, T., Madry, R., Timorek, A., Stelmachów, J., Karpińska, G., Rembiszewska, A., Ziółkowska, I., Kraszewska, E., Debniak, J., Emerich, J., Ułańska, M., Płuzańska, A., Jedryka, M., Goluda, M., Chudecka-Głaz, A., Rzepka-Górska, I., Klimek, M., Urbański, K., Breborowicz, J., Zieliński, J., Markowska, J. Br. J. Cancer (2003) [Pubmed]
  11. Colocalization of BAX with BID and VDAC-1 in nimesulide-induced apoptosis of human colon adenocarcinoma COLO 205 cells. Godlewski, M.M., Gajkowska, B., Lamparska-Przybysz, M., Motyl, T. Anticancer Drugs (2002) [Pubmed]
  12. Enhanced P53 and BAX gene expression and apoptosis in A549 cells by cis-Pt(II) complex of 3-aminoflavone in comparison with cis-DDP. Kosmider, B., Wojcik, I., Osiecka, R., Bartkowiak, J., Zyner, E., Ochocki, J., Liberski, P. Investigational new drugs. (2005) [Pubmed]
  13. Hierarchical regulation of mitochondrion-dependent apoptosis by BCL-2 subfamilies. Kim, H., Rafiuddin-Shah, M., Tu, H.C., Jeffers, J.R., Zambetti, G.P., Hsieh, J.J., Cheng, E.H. Nat. Cell Biol. (2006) [Pubmed]
  14. PUMA mediates the apoptotic response to p53 in colorectal cancer cells. Yu, J., Wang, Z., Kinzler, K.W., Vogelstein, B., Zhang, L. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  15. Regulation of apoptosis proteins in cancer cells by ubiquitin. Zhang, H.G., Wang, J., Yang, X., Hsu, H.C., Mountz, J.D. Oncogene (2004) [Pubmed]
  16. Characterization of distinct consecutive phases in non-genotoxic p53-induced apoptosis of Ewing tumor cells and the rate-limiting role of caspase 8. Kovar, H., Jug, G., Printz, D., Bartl, S., Schmid, G., Wesierska-Gadek, J. Oncogene (2000) [Pubmed]
  17. Analysis of apoptosis and expression of bcl-2 gene family members in the human and baboon ovary. Kugu, K., Ratts, V.S., Piquette, G.N., Tilly, K.I., Tao, X.J., Martimbeau, S., Aberdeen, G.W., Krajewski, S., Reed, J.C., Pepe, G.J., Albrecht, E.D., Tilly, J.L. Cell Death Differ. (1998) [Pubmed]
  18. The potential role of BAX and BCL-2 expression in diffuse alveolar damage. Guinee, D., Brambilla, E., Fleming, M., Hayashi, T., Rahn, M., Koss, M., Ferrans, V., Travis, W. Am. J. Pathol. (1997) [Pubmed]
  19. Low-dose fractionated radiation potentiates the effects of Paclitaxel in wild-type and mutant p53 head and neck tumor cell lines. Dey, S., Spring, P.M., Arnold, S., Valentino, J., Chendil, D., Regine, W.F., Mohiuddin, M., Ahmed, M.M. Clin. Cancer Res. (2003) [Pubmed]
  20. Requirement of BAX for efficient adenovirus-induced apoptosis. Lomonosova, E., Subramanian, T., Chinnadurai, G. J. Virol. (2002) [Pubmed]
  21. Germ line BAX alterations are infrequent in Li-Fraumeni syndrome. Barlow, J.W., Mous, M., Wiley, J.C., Varley, J.M., Lozano, G., Strong, L.C., Malkin, D. Cancer Epidemiol. Biomarkers Prev. (2004) [Pubmed]
  22. Glutathione levels and BAX activation during apoptosis due to oxidative stress in cells expressing wild-type and mutant cystic fibrosis transmembrane conductance regulator. Jungas, T., Motta, I., Duffieux, F., Fanen, P., Stoven, V., Ojcius, D.M. J. Biol. Chem. (2002) [Pubmed]
  23. Attenuation of caspase-3-dependent apoptosis by Trolox post-treatment of X-irradiated MOLT-4 cells. Inanami, O., Takahashi, K., Kuwabara, M. Int. J. Radiat. Biol. (1999) [Pubmed]
  24. BAX enhances paclitaxel-induced apoptosis through a p53-independent pathway. Strobel, T., Swanson, L., Korsmeyer, S., Cannistra, S.A. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  25. BAX-induced cell death may not require interleukin 1 beta-converting enzyme-like proteases. Xiang, J., Chao, D.T., Korsmeyer, S.J. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  26. Apoptotic response to oncogenic stimuli: cooperative and antagonistic interactions between c-myb and the growth suppressor p53. Sala, A., Casella, I., Grasso, L., Bellon, T., Reed, J.C., Miyashita, T., Peschle, C. Cancer Res. (1996) [Pubmed]
  27. Impaired BAX protein expression in breast cancer: mutational analysis of the BAX and the p53 gene. Sturm, I., Papadopoulos, S., Hillebrand, T., Benter, T., Lück, H.J., Wolff, G., Dörken, B., Daniel, P.T. Int. J. Cancer (2000) [Pubmed]
  28. BAX-dependent transport of cytochrome c reconstituted in pure liposomes. Saito, M., Korsmeyer, S.J., Schlesinger, P.H. Nat. Cell Biol. (2000) [Pubmed]
  29. LATS1 tumor suppressor regulates G2/M transition and apoptosis. Xia, H., Qi, H., Li, Y., Pei, J., Barton, J., Blackstad, M., Xu, T., Tao, W. Oncogene (2002) [Pubmed]
  30. Embryo quality and production efficiency of porcine parthenotes is improved by phytohemagglutinin. Gupta, M.K., Uhm, S.J., Han, D.W., Lee, H.T. Mol. Reprod. Dev. (2007) [Pubmed]
  31. MCL-1 inhibits BAX in the absence of MCL-1/BAX Interaction. Germain, M., Milburn, J., Duronio, V. J. Biol. Chem. (2008) [Pubmed]
  32. An informatics approach identifying markers of chemosensitivity in human cancer cell lines. Amundson, S.A., Myers, T.G., Scudiero, D., Kitada, S., Reed, J.C., Fornace, A.J. Cancer Res. (2000) [Pubmed]
  33. Structural basis of BFL-1 for its interaction with BAX and its anti-apoptotic action in mammalian and yeast cells. Zhang, H., Cowan-Jacob, S.W., Simonen, M., Greenhalf, W., Heim, J., Meyhack, B. J. Biol. Chem. (2000) [Pubmed]
  34. Transcriptional activation by the Kaposi's sarcoma-associated herpesvirus latency-associated nuclear antigen is facilitated by an N-terminal chromatin-binding motif. Wong, L.Y., Matchett, G.A., Wilson, A.C. J. Virol. (2004) [Pubmed]
  35. Microsatellite instability in colorectal cancer. Söreide, K., Janssen, E.A., Söiland, H., Körner, H., Baak, J.P. The British journal of surgery. (2006) [Pubmed]
  36. Smooth muscle cell apoptosis in primary varicose veins. Urbanek, T., Skop, B., Wiaderkiewicz, R., Wilczok, T., Ziaja, K., Lebda-Wyborny, T., Pawlicki, K. European journal of vascular and endovascular surgery : the official journal of the European Society for Vascular Surgery. (2004) [Pubmed]
  37. Coexpression of genes involved in apoptosis in central nervous system neoplasms. Bruggers, C.S., Fults, D., Perkins, S.L., Coffin, C.M., Carroll, W.L. J. Pediatr. Hematol. Oncol. (1999) [Pubmed]
  38. Apoptosis-related proteins, BCL-2, BAX, FAS, FAS-L and PCNA in liver biopsies of patients with chronic hepatitis B virus infection. Ehrmann, J., Galuszková, D., Ehrmann, J., Krc, I., Jezdinská, V., Vojtések, B., Murray, P.G., Koláo, Z. Pathol. Oncol. Res. (2000) [Pubmed]
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